Diabetes elevated liver enzymes

Glycogenic Hepatopathy in Type 1 Diabetes Mellitus

Abstract

Glycogenic hepatopathy is a rare cause of high transaminase levels in type 1 diabetes mellitus. This condition, characterized by elevated liver enzymes and hepatomegaly, is caused by irreversible and excessive accumulation of glycogen in hepatocytes. This is a case report on a 19-year-old male case, diagnosed with glycogenic hepatopathy. After the diagnosis was documented by liver biopsy, the case was put on glycemic control which led to significant decline in hepatomegaly and liver enzymes. It was emphasized that, in type 1 diabetes mellitus cases, hepatopathy should also be considered in the differential diagnoses of elevated liver enzyme and hepatomegaly.

1. Introduction

Liver enzyme elevation is more common among diabetic patients compared to the general population. This condition is often associated with nonalcoholic hepatosteatosis . Another very rare cause of elevated liver enzymes, especially among type 1 diabetic patients, is glycogenic hepatopathy (GH). GH develops due to excessive and irreversible accumulation of glycogen in the hepatocytes and causes liver function disorders and hepatomegaly . Mauriac first defined GH in a child with brittle diabetes, as a component of Mauriac syndrome, characterized by delayed development, hepatomegaly, cushingoid appearance, and delayed puberty . Additionally, GH can also be observed in adult type 1 diabetic individuals without other components of Mauriac syndrome . Hyperglycemia and overinsulinization (poor glycemic control) are believed to be metabolic preconditions in GH. GH therapy is performed via establishing glycemic control. Tight glycemic control via intensive insulin therapy provides full remission of clinical, laboratory, and histological abnormalities . Here, a 19-year-old case diagnosed with GH is presented with a discussion referenced to the medical literature.

2. Case

A 19-year-old male patient was admitted to the emergency department due to loss of appetite and nausea complaints that continued for two days. The medical history of the case showed that he was followed up due to type 1 diabetes for 8 years and for hepatosteatosis for 3 years, had poor blood glucose regulation despite insulin analogue and basal insulin therapy, and was hospitalized and followed up 8–10 times for diabetic ketoacidosis. He did not have any outstanding condition in family history. His arterial blood pressure was measured as 90/50 mmHg and pulse as 92 beat/min and body temperature was 36.9°C in his physical examination. At his abdominal examination, liver was palpable 4 cm below the costal margin, and no splenomegaly or acid was determined. The cardiovascular and respiratory system examination results were normal. The laboratory results of the case obtained in the emergency department were as follows: glucose 350 mg/dL, aspartate aminotransferase (AST) 603 IU/mL, alanine aminotransferase (ALT) 570 IU/mL, alkaline phosphatase (ALP) 921 U/L, and gamma glutamyl transferase (GGT) 379 U/L. Ketone was positive in his full urinalysis but there was no evidence of acidosis in his arterial blood sample (pH: 7.38; bicarbonate 22 mEq/L). The case was hospitalized with diabetic ketosis and liver function disorder diagnoses and was put on intravenous liquid and insulin replacement for the treatment of diabetic ketosis. On the 36th hour of his hospitalization, urine ketone was negative and nausea had regressed. The patient was then started on intensive insulin therapy. He had elevated aminotransferase and hepatomegaly. Abdominal ultrasonography results yielded the fact that the liver was 24 cm and the parenchyma appeared concordant with grade II hepatosteatosis.

The history of the case included elevated liver enzymes for 3 years and hepatosteatosis. It was recorded that the liver enzymes had great fluctuations within the past 3 years, he was hospitalized due to hyperglycemia or ketoacidosis, and his liver enzymes declined when his blood sugar was regulated. The patient who did not have a history of hepatotoxic agent use was examined with regard to chronic hepatitis differential diagnosis since the aminotransferase levels were found to be elevated to more than 10 times the normal values, intermittently for 3 years. Serologic and biochemical investigations for chronic viral hepatitis, hemochromatosis, Wilson’s disease, autoimmune hepatitis, and/or overlap syndromes had normal results (Table 1). Thereupon, a liver biopsy was performed. Significant widespread macrovesicular fatty changes in the hepatocytes and focal intranuclear clearing were observed in the histopathological examinations. No fibrosis or inflammation was detected (Figure 1). Strong intracytoplasmic PAS staining was observed in favor of glycogen in the histochemical investigations (Figure 2). After diastase digestion, which selectively degrades glycogen, PAS staining was no longer positive, confirming that glycogen accumulation was responsible for the findings (Figure 3).

Parameter Results
HbSAg Negative
Anti-Hbc IgG Negative
Anti-HCV Negative
Ferritin 200 ng/mL
Iron 41 µg/dL
Total iron binding capacity 216 µg/dL
Urine Cu/24 hours 17 µg
Ceruloplasmin 35 mg/dL
Alpha-1 antitrypsin 123 mg/dL
ANA (anti-nuclear antibody) Negative
AMA M2 (anti-mitochondrial antibody) Negative
Anti-SMA (anti-smooth muscle antibody) Negative
ANCA (anti-nuclear cytoplasmic antibody) Negative

Table 1 Laboratory tests conducted for differential diagnosis of chronic hepatitis.
Figure 1 Histological findings in the liver (hematoxylin and eosin stain). The hepatocytes are diffusely swollen with rarefaction of cytoplasm and accentuation of the cell membranes. Numerous hepatocytes exhibit glycogenated nuclei. There are fatty droplets presenting without inflammation and fibrotic changes.
Figure 2 Histological findings in the liver (Periodic Acid-Schiff (PAS) stain). Cross section without showing zonal distribution pattern, having the macrovesicular steatosis and hydropic degeneration. In some areas PAS histochemical analysis showed hepatocyte cytoplasm filled with glycogen and glycogenic core (PAS, original size ×40).
Figure 3 Histological findings in the liver (Periodic Acid-Schiff (PAS) stain) after diastase digestion. The hepatocyte cytoplasm is not stained with PAS.

The case was diagnosed with GH due to the present clinical, laboratory, and pathological findings. A significant decline was observed in the liver enzymes (aspartate aminotransferase (AST) 77 IU/mL, alanine aminotransferase (ALT) 73 IU/mL, alkaline phosphatase (ALP) 139 U/L, and gamma glutamyl transferase (GGT) 133 U/L) and the liver size (measured as 19 cm in the control abdominal ultrasonography) with a 3-week diet and intensive insulin therapy (1 IU/kg).

3. Discussion

The prevalence of elevated liver enzymes has increased among diabetic patients. The prevalence of elevated alanine aminotransferase level is 9.5% among type 1 and 12.1% among type 2 diabetics. These percentages are higher than those expected in a general population (2.7%) . Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease for both the general and the diabetic populations today. Obesity and metabolic syndrome play major roles in NAFLD pathogenesis. Therefore, it is observed more frequently in type 2 diabetes cases compared to type 1 . On the other hand, it should be noted that NAFLD is a diagnosis of exclusion . The case presented was followed up for the past three years with NAFLD diagnosis due to elevated liver enzyme levels and ultrasonographic hepatosteatosis appearance. The extreme elevation (over 10 times the normal values) of the liver enzyme levels of our case, who was a type 1 diabetic, was a trigger for investigating secondary causes. Autoimmune hepatitis, which can accompany toxic hepatitis, chronic viral hepatitis, Wilson’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, and type 1 diabetes, was ruled out serologically and biochemically. Afterwards, the case was diagnosed with GH upon liver biopsy.

GH, a disease that develops due to hepatic glycogen accumulation, is characterized by hepatomegaly and elevated liver enzyme levels . GH was first defined as glycogen accumulation in 1930, as a component of Mauriac syndrome (type 1 diabetes, delayed development, hepatomegaly, cushingoid appearance, and delayed puberty) . However, GH can also be observed in adult type 1 diabetic individuals without other components of Mauriac syndrome . Type 1 diabetes patients compose majority of the case reports on this rare condition. At the same time, there are reports in the medical literature of development of this condition in three children who were not diabetic and in one dumping syndrome case that did not have glucose intolerance .

Hyperglycemia and overinsulinization are believed to be metabolic preconditions for hepatic glycogen accumulation in GH. Hyperglycemia activates glycogen synthase by inhibiting glycogenesis via glycogen phosphorylation inactivation. Glycogen accumulation further increases because insulin also activates glycogen synthase . A study conducted in rats with insulin deficiency has shown that, after a single dose of insulin injection, glycogenesis continues for a significant amount of time after blood glucose levels return to the preinjection levels . In other words, hepatic glycogen accumulation occurs despite the high cytoplasmic glucose concentration in the presence of insulin. Therefore, frequent hyperglycemic episodes and the following insulin therapies are believed to be the primary pathogenetic mechanisms of hepatomegaly and liver function disorder that develop in type 1 diabetic patient due to glycogen accumulation. Yet, it is not clear why this pathogenetic mechanism develops in a small patient group. One of the hypotheses on this matter was the defect in the genes that code the proteins that regulate the glycogen synthase and/or glucose 6-phosphatase activity . GH therapy is performed via establishing glycemic control. Tight glycemic control, provided via intensive insulin therapy, results in full remission of clinical, laboratory, and histologic abnormalities . It has been reported in the medical literature that remission was attained in a case with GH by a continuous insulin infusion pump implanted under the skin . Similarly, the case presented here also attained blood glucose regulation, accompanied by reduction in the liver size and significant decreases in ALT and AST levels with intensive insulin therapy. Control liver biopsy was not performed in this case after laboratory and radiological improvements; therefore, histologic remission was not valuated. The fact that the liver enzymes could not return to the normal ranges was believed to be associated with the hepatosteatosis accompanying GH in this case.

Consequently, liver enzyme elevation is a common condition among diabetic patients. Though often NAFLD is responsible for this condition, in case of type 1 diabetic patients, GH should be considered for differential diagnosis in the presence of severe elevation of aminotransferase levels.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

An Unusual Cause of Elevated Liver Enzymes in a Diabetic Patient

Histologic evaluation of the liver biopsy showed diffusely pale, swollen hepatocytes that often compressed the sinusoids. Pale swelling of hepatocytes was owing to marked glycogen accumulation, which was demonstrated by a strongly positive Periodic acid-Schiff staining (Figure BFigure B), that disappeared after digestion with diastase (Figure CFigure C). The presence of abundant glycogen deposition in the hepatocyte cytoplasm (Figure DFigure D, arrows) and in some nuclei was confirmed by electron microscopy as electron-dense granules. The biopsy was negative for steatosis and fibrosis. The finding of abundant glycogen deposition in hepatocytes associated with poorly controlled diabetes and dramatic response to glycemic control confirms the diagnosis as glycogenic hepatopathy. There were no features to suggest hypoxic hepatitis, which had been suspected clinically.

Glycogenic hepatopathy was first described by Maauriac in 1930,1x1Torbenson, M., Chen, Y.Y., Brunt, E. et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol. 2006; 30: 508–513
Crossref | PubMed | Scopus (128) | Google ScholarSee all References as a rare syndrome in diabetic children including growth retardation, hepatomegaly, cushingoid features, and delayed puberty. However, this entity can present in the absence of Maauriac syndrome changes. Therefore, glycogenic hepatopathy poses diagnostic challenges to clinicians and is infrequently diagnosed based on its rarity and lack of its awareness.1x1Torbenson, M., Chen, Y.Y., Brunt, E. et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol. 2006; 30: 508–513
Crossref | PubMed | Scopus (128) | Google ScholarSee all References Glycogenic hepatopathy can be observed in adults or children with poorly controlled diabetes mellitus who are treated with insulin, usually in the setting of type 1 and rarely type 2 diabetes mellitus.1x1Torbenson, M., Chen, Y.Y., Brunt, E. et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol. 2006; 30: 508–513
Crossref | PubMed | Scopus (128) | Google ScholarSee all References The key findings of glycogenic hepatopathy are the presence of clinical features (hepatomegaly and elevated transaminases) together with distinct biopsy features (glycogen accumulation, no or mild fatty changes, no or minimal inflammation and no significant fibrosis).1x1Torbenson, M., Chen, Y.Y., Brunt, E. et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol. 2006; 30: 508–513
Crossref | PubMed | Scopus (128) | Google ScholarSee all References Glycogenic hepatopathy results from excessive accumulation of glycogen in hepatocytes owing to wide fluctuation in both blood glucose and insulin levels. High glucose levels cause direct flow of glucose into hepatocytes where glucose is rapidly phosphorylated, and then trapped in hepatocytes. Prolonged hyperglycemia treated with insulin promotes excessive conversion of glucose to glycogen.2x2Ferrer, J.C., Favre, C., Gomis, R.R. et al. Control of glycogen deposition. FEBS Lett. 2003; 546: 127–132
Abstract | Full Text | Full Text PDF | PubMed | Scopus (156) | Google ScholarSee all References The prognosis of glycogenic hepatopathy is good with complete remission of liver problems after adequate management of insulin and glucose levels.3x3Fridell, J.A., Saxena, R., Chalasani, N.P. et al. Complete reversal of glycogen hepatopathy with pancreas transplantation: two cases. Transplantation. 2007; 83: 84–86
Crossref | PubMed | Scopus (24) | Google ScholarSee all References

The liver is one of the most important organs in our bodies, playing a central role in a number of important processes.

One of these is to help control glucose concentration in the blood (i.e. regulating blood glucose levels).

A healthy liver helps keep blood glucose within the ‘normal range’ and protects against excessive fluctuations, which is vital as high blood sugar (hyperglycemia) and low blood sugar (hypoglycemia) can both be dangerous for the human body.

What is the liver?

The liver is the largest internal organ of the human body, weighing approximately 1.4 kg (3 lb) in the average adult.

Located under your diaphragm (more to the right side of your body), it is a wedge-shaped, spongy organ that performs a number of key functions, including regulating blood sugar levels, getting rid of toxins (body detoxification) and bile production.

It also acts as a major filter of the blood travelling from the digestive tract to the rest of the body.

The liver’s response to stress

The body responds to stress by releasing hormones from the adrenal glands within the kidneys. These hormones travel within the blood to the liver and trigger the liver to release some of its stored glycogen.

Release of glucose into the blood is part of the body’s ‘fight or flight’ response, preparing the body with energy to be able to quickly respond to a threat or stressful situation.

  • Read more on stress and blood glucose levels

The liver’s response to exercise

During exercise, or other forms of physical activity, the liver plays a part in regulating blood glucose levels.

When you begin physical activity, glycogen from the muscles are mobilised to be used as a source of fuel.

As glucose is taken up by the muscles, the liver releases glucose into the blood.

The liver can only store a certain amount of glucose and so if strenuous exercise is sustained, the body will need to get its energy from other sources.

When the liver has released its glucose stores, the body will break down fats which are converted into another source of fuel, ketones, by the liver.

The liver and cholesterol

The liver is responsible for regulating cholesterol levels in the blood. The liver is able to produce and release cholesterol into the blood and also can remove cholesterol from the bloodstream. When cholesterol is removed from the blood, the liver converts cholesterol into bile salts.

  • Read more on cholesterol and the body

Liver damage

A damaged liver can cause a number of serious health problems as it is responsible for so many important functions of the human body.

A common sign of a damaged liver is a condition called jaundice, which is a yellowness of your skin and eyes that occurs when bilirubin – a yellow breakdown product of your red blood cells – builds up in the blood.

If left untreated, the damage could become severe enough to stop the liver functioning altogether, in which case you would have less than a day to live.

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is a diabetes-related condition which causes the build-up of excess fat in your liver.

This condition occurs in at least 50 per cent of people with type 2 diabetes and close to half of those with type 1 diabetes , and, unlike other liver problems, is not linked to alcohol consumption.

The risk of developing this disease is increased by the presence of diabetes, as well also increased by other medical conditions related to diabetes, including:

  • Obesity
  • High blood pressure (hypertension) and
  • High cholesterol

The presence of non-alcoholic fatty liver disease is known to raise the risk of liver inflammation or scarring (cirrhosis), and is also associated with an increased risk of liver cancer and heart disease.

If you are diabetic and are diagnosed with non-alcoholic fatty liver disease, your GP may recommend an ultrasound inspection of your liver upon diagnosis, followed by regular blood tests to monitor your liver function.

  • Read more on non-alcoholic fatty liver disease

Looking after your liver

If you have diabetes, there are a number of steps you can take to protect your liver and prevent non-alcoholic fatty liver disease from occurring. These include:

  • Good management of your blood sugar levels , with the help of your health care team
  • Losing weight , if needed, and maintaining a healthy weight through a healthy diet and regular exercise
  • Keeping blood pressure within recommended limits
  • Keeping your low-density lipoprotein (LDL or “bad”) cholesterol and triglycerides levels low
  • Cutting your alcohol intake

Elevated Liver Enzymes

Liver and other organs in the abdomen

What does the liver do and what are elevated liver enzymes?

The liver is the body’s largest internal organ. It is located below the diaphragm on the right side of the abdomen. The liver performs many functions, including the following:

  • Produces most of the proteins the body needs
  • Metabolizes (breaks down) nutrients from food to produce energy
  • Prevents shortages of nutrients by storing certain vitamins, minerals, and sugar
  • Produces bile, a substance that helps digest fat and absorb vitamins A, D, E, and K
  • Produces substances that help with blood clotting
  • Helps your body fight infection by removing bacteria from the blood
  • Removes potentially poisonous byproducts of certain medications

What are liver enzymes?

An enzyme is a chemical that accelerates (speeds up) chemical reactions within the body. There are several enzymes in the liver, including alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT). Elevated liver enzymes, found with a blood test, indicate inflamed or injured liver cells.

Why does a doctor check for elevated liver enzymes?

A doctor may order a liver enzyme test if a patient is being treated for liver disease or has a higher risk for liver disease. For instance, if the liver is injured, ALT is released into the bloodstream, and levels of this enzyme would be elevated.

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Definition

A liver enzyme is a protein that helps to speed up a chemical reaction in the liver. Liver function tests are blood tests that are used to evaluate various functions of the liver – for example, metabolism, storage, filtration and excretion, which are often performed by liver enzymes. However, not all liver function tests are measures of enzyme function.

Description

The liver is an important internal organ because it performs many functions. It helps detoxify the many toxins in the body, makes proteins that are used to help clot the blood (clotting factors) and other proteins that help draw fluid into our blood vessels (e.g., albumin).

Liver function tests are blood tests that include alkaline phosphatase, prothrombin time (PT, a measure of blood clotting), serum bilirubin and serum albumin. The most commonly used indicators of liver damage are the alanine aminotransferase (ALT) and aspartate aminotransferase (AST), formally referred to as SPGT and SGOT. These are enzymes normally found in liver cells that leak out of these cells and make their way to the blood when liver cells are injured. The ALT is felt to be a more specific indicator of liver inflammation, as AST is also found in other organs, such as the heart and skeletal muscle.

In acute injury to the liver, as in viral hepatitis, the level of the ALT and AST may be used as a general measure of the degree of liver inflammation or damage. In chronic liver disease, this is not the case, for these enzymes may be entirely within the normal range, even in the presence of cirrhosis (scarring of the liver).

Increased levels of ALT and AST can have a large number of clinical implications. Elevated levels might involve hepatocellular disease, active cirrhosis, metastatic liver tumor, infection or toxic hepatitis, severe burns, pancreatitis, myocardial infarction (heart attack), trauma, severe burns, acute hemolytic anemia, crushing injuries, gangrene or shock.

Alkaline phosphatase is the most frequently used test to detect obstruction in the biliary system. Elevation of this enzyme may be found in a large number of disorders as common as gallstone disease, alcohol abuse and drug-induced hepatitis, or in less common disorders, such as primary biliary cirrhosis or biliary tumors. Although this enzyme is found both in the liver and the bile, it leaks into the bloodstream in a manner similar to that of the ALT and AST. Alkaline phosphatase is also found in other organs, such as bone, placenta and intestine.

Prothrombin time (PT) is a one measure of blood clotting. It may be elevated when there is damage to the liver, meaning that there is a greater tendency to bleed. PT is also used to monitor the appropriate dose of coumadin (warfarin) for certain patients who need blood-thinners (anti-coagulation).

Low serum albumin may cause blood vessels to be leaky and allow fluid to accumulate in the abdomen (ascites) or elsewhere in the body.

Serum bilirubin is usually elevated in patients with jaundice.

Questions

What are the normal ranges of these enzymes?

Are the enzymes slightly elevated or severely elevated?

What is the cause of the elevated liver enzymes?

Does the enzyme elevation mean inflammation to the liver or damage to the liver?

If the elevated enzymes indicate damage to the liver, how much damage has occurred?

Liver Disease—What You Need to Know About this Common Problem of Diabetes

With James H. Tabibian, MD, PhD, Kenneth Cusi, MD, and Dimitrios A. Koutoukidis, PhD, RD

Of all the known complications of type 2 diabetes, hearing “You have fatty liver disease,” likely comes as a shocking, unpleasant surprise, and no one that is expected or familiar. About one in three people in the United States has the condition. Another common cause of chronic liver disease is obesity.1

Having this form of chronic liver disease is often discovered by chance, perhaps when blood tests find elevated levels of liver enzymes.1 And the diagnosis is not uncommon, says James H. Tabibian, MD, PhD, assistant professor of medicine with a specialty in gastroenterology at the University of California/Davis, who says he is frequently having to give many patients this news.

Type 2 diabetes and obesity are 2 main causes of fatty liver disease. Image: 123rf

Liver Disease Commonly Occurs if You Have Type 2 Diabetes or Obesity

Medically, the formal name for this condition involving the liver is: nonalcoholic fatty liver disease, or NAFLD.

Chronic fatty liver disease occurs because of a buildup of excess lipids in liver cells that arises for reasons other than consuming too much alcohol, which causes a different form of liver disease. While the liver normally contains some fat, when fat accumulates to more than 5-10% of the liver’s weight, the disorder is termed chronic fatty liver disease.1

The reaction of patients, Dr. Tabibian tells EndocrineWeb, varies greatly. “For some, the diagnosis sounds esoteric and bizarre and they may blow it off as something of little consequence,” perhaps ditching doctor’s appointments that are important to monitor any changes in severity of NAFLD over time, he says.

“Others want to grab the bull by the horns,” he says, and make the critical lifestyle changes necessary to forestall progression of the disease. “Unless weight loss is achieved, this worsens gradually over time,” he says. “So anything you can do to prevent the disease from advancing is strongly urged, and the sooner the better.”

Fortunately, receiving a diagnosis of non-alcoholic fatty liver disease is not so dire, says Dr. Tabibian. One of the best steps you can take is heed your doctors suggestion of a referral to attend an organized, structured weight loss program. 2 That was the bottom-line conclusion from a study reported by a team of researchers from the United Kingdom (UK) who evaluated results of 22 previously published studies, an approach known as a systematic review of the literature and meta-analysis.2

To accompany the study, Dr. Tabibian, with coauthors Elizabeth S. Aby, MD and Jihane Benhammou, MD, wrote a patient information page to spell out other actions that anyone who is newly diagnosed with fatty liver can take.3

Why Losing Weight Takes Center Stage is Addressing Liver Disease

The UK researchers considered the treatments of more than 2,500 men and women with NFALD, who were on average 45 years old. The question: Can weight loss help improve non-alcoholic fatty liver disease?

The researchers looked at weight loss and also at certain biomarkers, or indications of fatty liver, such as levels of a liver enzyme known as ALT (alanine aminotransferase). What they found is that in people who did not attempt to lose weight or tried with a standard weight loss diet were not very successful but those who participated in a more intensive program showed greater weight change and with it, improvement in their liver status.2

In fact, individuals who attended a structured or formal weight management program lost about 8 pounds more, over about 6 months, than those who didn’t try or relied on their own to lose weight.2 When people lost weight, they showed a marked improvement in liver tests, such as ALT, and other parameters of liver health.

Exactly how the weight loss improves liver health is not known for sure, the researchers say. It could be that by improving control of blood sugar levels and reducing problems of insulin resistance may explain the positive changes in liver function, says study leader Dimitrios A. Koutoukidis, PhD, RD, a researcher at the University of Oxford. This is important since about half of those with type 2 diabetes have NFALD, as shown from results of other research.4

What Do You Need to Know if You Have Non-Alcoholic Fatty Liver Disease

If your doctor diagnoses you with NAFLD, don’t ignore it. It’s very important to accept the urgency of reversing fatty liver disease, so it doesn’t progress to the most severe form known as NASH (non-alcoholic steatohepatitis), and up to 25% of those with NASH may have cirrhosis or scarring of the liver.1

Attending a formal weight loss program assures the best outcomes in someone with fatty liver disease, related to type 2 diabetes and overweight. Image: 123rf

As this liver condition progresses, you may also experience other symptoms such as trouble concentrating, increased forgetfulness, confusion and greater daytime sleepiness.3

At present, there is no specific drug available to treat available fatty liver disease, the best and only way to lessen your risks is to adopt lifestyle changes that include weight loss: the same recommendations as you’ve likely heard about or considered to management your diabetes and/or body weight.

Six Strategies to Improve Liver Disease

Dr. Tabibian and his colleagues share several key points that will not only help you improve your liver status but will similarly benefit you if you have type 2 diabetes and/or a body mass index of 25 kg/m2 or higher, 3 as follows:

  • Just by losing 10% of your current body weight will be enough to reduce liver fat and lessen the harmful inflammation. If you’ve tried diet and exercise but this approach hasn’t been enough to help you get to that goal, consider discussing weight loss medications or even weight loss surgery.
  • Adjust your meals to more closely reflect the Mediterranean diet, an approach to eating that is features mostly unprocessed (Fresh or frozen) vegetables and fruits, and limits fats to olive oil and nuts.
  • Avoid foods and drinks high in fructose, such as artificially sweetened sodas, juices and desserts, might go a long way in lowering the level of liver fat. Better yet, don’t drink your calories.
  • Exercising is strongly recommended—Build up to at least 150 minutes a week—or aim for 10,000 to 15,000 steps a day, based on your doctor’s advice.
  • Limiting alcohol (to 1 drink daily for women, and 2 at most for men) is suggested. Ask your doctor what limit is best for you.
  • To further protect the liver, ask your doctor about your need for hepatitis A and B vaccinations, if you are not already immune.

Endorsing the Benefits of Weight Loss to Improve Overall and Liver Health

Putting into place a plan to lower your body weight is highest on the list of healthy strategies needed to tackle fatty liver disease and overweight, agrees Kenneth Cusi, MD, FACE, FACP, chief of the division of endocrinology, diabetes and metabolism at the University of Florida, Gainesville, who was not involved in the study.

“It really boils down to losing at least 7% of weight to reduce the inflammation,” he says. And if there is scarring, meaning the NFALD has progressed, ”you probably need to lose closer to 10% of your initial weight.”

In general, the research results have shown that enrolling in structured weight loss programs that include repeat visits and ongoing reinforcement work best for meaningful weight management, says Dr. Cusi. Why these programs work in individuals with fatty liver disease in helping to recover liver health is sparse; still, any weight loss will be a great good step toward improving many aspects of your health.

Updated on: 07/15/19 Continue Reading When Your Doctor Suggests Healthier Eating for Weight Loss: Which Diet Plan? View Sources

  1. American Liver Foundation. The Facts About Non-Alcoholic Fatty Liver Disease. Available at: https://liverfoundation.org/the-facts-about-non-alcoholic-fatty-liver-disease/. Accessed July 10, 2019.
  2. Koutoukidis DA, Astbury NM, Tudor KE, et al. Association of Weight Loss Interventions with Changes I Biomarkers of Nonalcoholic Fatty liver Disease: A Systematic Review and Meta-Analysis. JAMA Intern Med. 2019; ahead of print. Available at: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2737321. Accessed July 5, 2019.
  3. Aby ES, Benhammou JN, Tabibian JH. My Doctor Told Me I Have Fatty Liver—What Do I Need to Know? JAMA Internal Medicine. 2019; ahead of print. Available at: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2737322. Accessed July 10, 2019.
  4. Portillo-Sanchez P, Bril F, Maximos M, et al. High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. J Clin Endocrinol Metab. 2015;100 (6):2231-2238.

Elevated liver enzyme levels linked to higher gestational diabetes risk

The liver plays an important role in regulating glucose levels in the body. The liver enzyme, called gamma-glutamyl transferase (known as GGT), is a common marker of liver function and has also been associated with insulin resistance, which can be a precursor to gestational diabetes and type 2 diabetes.

“Several biomarkers appear to be associated with the risk of gestational diabetes,” said Monique M. Hedderson, PhD, senior author of the study and research scientist with the Kaiser Permanente Division of Research in Oakland, Calif. “This study and others we’ve done provide evidence that women who develop gestational diabetes have metabolic abnormalities even before pregnancy. In the future, we could potentially try to prevent gestational diabetes by intervening before women get pregnant.”

Gestational diabetes, or glucose intolerance during pregnancy, has increased dramatically in recent decades and is now one of the most common complications of pregnancy. It can lead to the birth of larger-than-normal babies and subsequent delivery complications. According to recent studies, women with gestational diabetes are seven times more likely to develop type 2 diabetes later in life, and their children are at greater risk of becoming obese and developing diabetes themselves.

Researchers examined the medical records of 256 women who developed gestational diabetes during pregnancy and compared them with 497 women who did not. Those studied had voluntarily given blood samples between 1985 and 1996 during routine care and subsequently delivered an infant in Kaiser Permanente’s Northern California region.

After adjusting for numerous possible confounding factors, including body mass index and alcohol use, the researchers found that women in the highest quartile of GGT had nearly twice the risk of subsequent gestational diabetes than those in the lowest quartile. No associations were found with two other commonly monitored liver enzymes, alanine aminotransferase and aspartate aminotransferase.

“A few studies have looked at liver enzyme levels during pregnancy and the risk of gestational diabetes, but to our knowledge this is the first to look at liver enzyme levels measured before pregnancy,” said lead author Sneha Sridhar, MPH, project coordinator with the Kaiser Permanente Division of Research.

This study is the third in a series using the same cohort of mothers to examine the role of biomarkers prior to pregnancy in predicting the risk of gestational diabetes. The researchers ultimately hope to develop a risk model to help identify women who would benefit from interventions during the pre-conception period.

In the previous studies, researchers reported that:

  • Overweight women with low levels of the hormone adiponectin prior to pregnancy were nearly seven times more likely to develop gestational diabetes than normal weight women with high levels (August 2013).
  • Women with low levels of the sex hormone binding globulin were five times more likely to develop gestational diabetes than those with higher levels of the protein (February 2014).

New treatment for fatty liver disease and type 2 diabetes burns up fat in liver

In a study involving 86 people with varying degrees of fatty liver disease, researchers from KTH Royal Institute of Technology’s Science for Life Laboratory (SciLifeLab) research center and Gothenburg University found that the liver has the ability to burn up accumulated fats. The researchers propose a mixture of substances that will set this process in motion.

One of the most common chronic liver problems in the world, the accumulation of fat in the liver — or hepatic steatosis — is the key characteristic of non-alcoholic fatty liver disease (NAFLD). It is linked to obesity, insulin resistance, type 2 diabetes and cardiovascular diseases. Up to 30 percent of subjects with NAFLD develop non-alcoholic steatohepatitis (NASH) in which hepatic inflammation and scarring can lead to cirrhosis and liver cancer.

The researchers mapped the metabolic changes caused by accumulated fat in 86 patients’ liver cells, and combined this data with an analysis of a genome-scale model of liver tissue. Doing so enabled them to identify the precise metabolic changes individual patients’ liver cells undergo due to fat.

The results were published in Molecular Systems Biology.

Lead author Adil Mardinoglu, a systems biologist at KTH and SciLifeLab fellow, is one of the researchers who had earlier established a connection between NAFLD and low levels of the antioxidant, glutathione (GSH). A proof of concept test showed that accumulated liver was burned off by treating human subjects with a “cocktail” that increases oxidation of fat and synthesis of the antioxidants.

Mardinoglu says the team’s metabolic modeling approach, which relied on data from Swedish-based Human Protein Atlas effort, can be used for a number of chronic liver diseases.

Based on the results from the study, an improved intervention using a portfolio of substances has been designed. “This mixture can potentially decrease the amount of the fat accumulated in the liver,” Mardinoglu says. “There is no such drug available at present and we are planning for further clinical trials later this year.”

The approach combines systems biology and clinical medicine in a manner not previously done. “The results are exciting, and we have now designed a mixture of substances that will boost the oxidation of fat and generate antioxidants in the liver tissue,” says senior co-author Jan Borén from University of Gothenburg.

The researchers believe that the mixture of substances could also be used to treat accumulated liver fat due to alcoholic fatty liver disease and type 2 diabetes. “Considering NAFLD and diabetes are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes, such a mixture of substances might also be used in the treatment of subjects with diabetes,” says co-author, Ulf Smith of University of Gothenburg.

Mathias Uhlén, director of the Human Protein Atlas project and co-author of the paper, says: “I am extremely pleased that the resource created through the Human Protein Atlas effort has been used in the analysis of clinical data obtained from NAFLD patients and that this analysis has led to the design of a mixture of substances that can be used for treatment of this clinically important patient group.

Type 2 Diabetes and Fatty Liver Disease

Non-alcoholic fatty liver disease is a group of conditions in which fat builds up in the liver, leading to inflammation of the cells where it is stored and causing the liver to get bigger. It can progress to more serious conditions, including fibrosis and cirrhosis of the liver.

Fatty liver disease “is so common. It’s present arguably in a majority of type 2 diabetics,” says Daniel Einhorn, MD, clinical professor of medicine at the University of California, San Diego and the medical director of the Scripps Whittier Diabetes Institute. “None of us thought about it more than about 10 years ago, then all of a sudden we discovered it and see it all the time.”

Fatty Liver Disease and Type 2 Diabetes: The Connection

Diabetes does not cause fatty liver disease. Instead, the two diseases tend to occur in the same people because the same conditions cause both problems. “So, it’s not the diabetes per se. People with diabetes also have obesity and insulin resistance, and so the fatty liver is thought to be part of that,” Dr. Einhorn explains.

Einhorn says that most cases of fatty liver disease do not cause any harm. However, since type 2 diabetes and obesity are so common in the United States, fatty liver disease is now a leading cause of end-stage (fatal) liver disease requiring a liver transplant, along with alcohol abuse and hepatitis.

Fatty Liver Disease Diagnosis

Fatty liver disease has no symptoms. People who are being treated for diabetes will have liver enzyme tests as part of their routine blood work during medical exams. Ninety-nine percent of the cases of fatty liver disease are detected by this test, says Einhorn. In some cases it will be picked up during the physical exam or in imaging studies, like a computed tomography scan of the abdomen or a liver ultrasound.

Einhorn says that fatty liver disease is not treated as a separate disease; therefore, doctors do not usually pin down the diagnosis with any additional studies unless liver enzymes are elevated unexpectedly, such as in a person without diabetes or obesity, or if the levels are very high and it appears that something else may be going on.

Fatty Liver Disease Treatment

There are no drugs that treat fatty liver disease. Instead, this condition is treated indirectly with lifestyle changes such as losing weight, getting in better physical shape, and controlling blood sugar and triglycerides — fats in the blood that can contribute to fatty liver. “You try to get the best possible control and hope that the fatty liver responds to that control,” says Einhorn.

Diabetes medications known as “insulin sensitizers” have been shown to have an effect in reducing fat in the liver; these include thiazolidinediones or glitazones such as pioglitazone (Actos) and rosiglitazone (Avandia), which are used to treat insulin resistance. It makes sense to use them if insulin resistance is part of fatty liver, explains Einhorn, but they are not U.S. Food and Drug Administration-approved for treating fatty liver disease.

Fatty Liver Disease Prevention

Type 2 diabetes, obesity, and fatty liver disease seem to go hand-in-hand. But it is not a given that if you have type 2 diabetes you will automatically develop fatty liver disease. Since obesity, insulin resistance, and high levels of triglycerides in the blood increase the risk of fatty liver disease, treating these other conditions can prevent its development.

Maintaining a healthy weight or losing weight if you are overweight or obese; exercising regularly; and controlling your blood sugar and triglyceride levels will go a long way toward safeguarding against fatty liver disease.

As many as 9 of 10 patients with obesity and type 2 diabetes have non-alcoholic fatty liver disease (NAFLD), and 20% of the general public has the same problem, making it the most common liver disease in the world. 1 Diabetes can also hasten the progression of the disorder to more serious hepatic conditions like cirrhosis and liver cancer. Although there is no well-documented treatment protocol for NAFLD, there is evidence to suggest that vitamin D deficiency may play a role in its development.

For example, hypovitaminosis D has been correlated with the histological changes of NAFLD. A meta-analysis has also found that patients with NAFLD are more likely than control subjects to have a vitamin D deficit. This evidence is also consistent with certain biochemical findings: The vitamin is known to play a role in hepatic metabolism through the VDR receptor, according to Ilaria Barchetta and associates at the Sapienza University of Rome. Finally, vitamin D appears to increase insulin sensitivity by means of free fatty acid flux modulation.

These lines of evidence suggest that vitamin D may be valuable as a therapeutic agent for patients with diabetes and fatty liver. To explore that possibility, Barchetta et al recruited 65 patients (26 to cholecalciferol, 29 to placebo) to participate in a randomized, double-blind, placebo-controlled study to determine if 2,000 IU a day of oral cholecalciferol for 24 weeks might improve hepatic function among patients with type 2 diabetes. They used reduction in hepatic fat fraction (HFF), measured by MRI, to assess the effects of the nutrient on the liver.

Although the vitamin supplement did raise serum vitamin D levels in the experimental group (48.15 + 23.7 to 89.90 + 23.6 nmol/L, P<0.001) there were no differences in hepatic fat, liver transaminase levels, or other parameters that might suggest the nutrient was improving patients’ fatty liver disease, including CK-18-M30 and P3NP, biomarkers that signal hepatic injury and fibrogenesis.

Since it may have been possible that the vitamin only benefits patients with a frank deficiency, the investigators also looked at the subset of patients with low serum vitamin D levels. Their report stated: “In order to investigate whether vitamin D supplementation may improve NAFLD exclusively in patients with hypovitaminosis D at the baseline, we performed an ancillary analysis to compare changes in the primary outcome from the baseline to 24-week including only patients with basal 25(OH)D <50 nmol/L, but again changes in HFF were not significantly different between treatment and placebo group in this subpopulation.”

Previous studies support these negative findings. Sharifi et al, for example, found that vitamin D supplements had no effects on aminotransferase levels, insulin resistance, or inflammatory markers in patients without diabetes who had fatty livers.2 Similarly when Kitson et al gave 25,000 IU per week to non-diabetics with non-alcoholic steatohepatitis for over 24 weeks, they were unable to document any changes in liver histology, liver biochemistry, or insulin resistance.3

Despite the negative findings from Barchetta et al, a few weaknesses in their methodology should be kept in mind. They studied only 65 patients. Such a small sample size means their conclusions may be subject to a Type 2 statistical error. It is also conceivable that 24 weeks of therapy may not have been long enough to have a positive impact on liver function.

During a recent email exchange with Medpage Today, Rohit Loomba, MD, chair of the American Liver Foundation Medical Advisory Committee and Professor of Medicine, Division of Gastroenterology at University of California, San Diego, pointed out that “Lower vitamin D levels are associated with more advanced NAFLD and more advanced fibrosis. However, replacement of vitamin D does not reverse liver disease in patients suffering from advanced form of NAFLD.” On the other hand, Loomba also emphasized that “If vitamin D levels are low we should replace them as they have other beneficial effects, but they do not prevent or halt progression of liver disease in humans.”

During a recent interview with Moises Nevah, MD, a gastroenterologist and hepatologist affiliated with McGovern Medical School at The University of Texas Health Science Center at Houston and the Memorial Hermann-Texas Medical Center, he reinforced one of the conclusions discussed in the Barchetta paper: “If there is a relationship between decreased vitamin D levels and fatty liver disease, exposure to vitamin D supplements may not have been sufficient enough to produce a clinically significant outcome. As the investigators propose, long-term studies are warranted.”

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