What is non-alcoholic fatty liver disease?
Non-alcoholic fatty liver disease is defined as liver fat >5 per cent in the absence of other identifiable causes. It is the most common cause of chronic liver damage in western countries and around 70 per cent of patients with type 2 diabetes have fatty livers.

Why is it a problem?
It increases the risk of non-alcoholic steatohepatitis and hepatocellular carcinoma (HCC). It can cause cirrhosis, and doubles the risk of both chronic kidney disease and cardiovascular disease.

What should pharmacists do to help?
Reducing visceral fat seems to be a particularly important intervention, as it is a strong risk factor for hepatic steatosis, inflammation and fibrosis. In patients with diabetes, statins may reduce HCC risk by 25-40 per cent.

Case Study
The effects of a fatty liver Patricia is a 46-year-old call-centre worker with a BMI of 30.7kg/m2, dyslipidaemia and a three-year history of type 2 diabetes. She’s receiving vildagliptin and simvastatin. Before starting vildagliptin, her liver enzyme levels were within the normal reference range.

Patricia tells you that she feels fatigued and weak, and reports that she’s beginning to lose weight. She wants to buy a tonic to give her a boost, and an OTC sleeping aid. Patricia thinks that her fatigue and weakness result from tiredness brought on by sleepless nights spent worrying about her financial problems and working overtime. After noting that her HbA1c control has declined in recent months, you refer her to her GP, who asks the diabetic clinic for a review.

Biopsy reveals that Patricia’s liver contains fat deposits and fibrosis. The hepatologist diagnoses non-alcoholic steatohepatitis.

A year later, Patricia presents to her GP with fluid retention and gastrointestinal bleeding, leading to the diagnosis of cirrhosis. She dies six years later from hepatocellular carcinoma.

Diabetes causes numerous well-known complications, including chronic kidney disease (CKD), heart disease and retinopathy. However, the increased risk of liver diseases such as non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) with diabetes is less well known.¹

Nevertheless, diabetes-related liver disease can prove fatal (NASH can cause a 10-fold rise in the risk of liver cancer),² increase the risk of developing ‘classic’ complications including retinopathy, and influence treatment choice.

Diabetes-related liver disease
Non-alcoholic fatty liver disease (NAFLD) is defined as liver fat >5 per cent in the absence of other identifiable causes such as alcohol abuse, viral hepatitis or certain medications including corticosteroids and oestrogen.¹ It is the most common cause of chronic liver damage in western countries.

Obese people and those with insulin resistance or diabetes are especially vulnerable to NAFLD.³ Indeed, around 70 per cent of patients with type 2 diabetes have fatty livers and NAFLD tends to be particularly aggressive in people with diabetes. Nevertheless, most diabetic NAFLD patients have normal liver transaminase levels.¹

Although fatty liver has traditionally been considered relatively benign,⁴ 20-30 per cent of people with NAFLD develop NASH.³ This is characterised by chronic necrosis, inflammation and, in many patients, fibrosis.¹

NASH can progress to cirrhosis, fatal liver failure and HCC.³ Around one in 200 NASH patients develop HCC within seven years.⁴

Despite these risks, healthcare professionals often overlook people with significant NASH due to the condition’s long, indolent clinical course.⁵ NASH causes few symptoms, there are few sensitive, non-invasive diagnostic tests, and liver function tests are often normal.¹

Fatty livers are both a cause and consequence of diabetes. Cirrhosis, for example, can cause diabetes,⁶ while diabetes increases mortality among patients with cirrhosis.⁷

Around 30 per cent of cirrhosis patients have concurrent diabetes.
Furthermore, more than 40 per cent and 17 per cent of patients with chronic hepatitis C infections show glucose intolerance and diabetes respectively, while 30-70 per cent have fatty livers.

Indeed, hepatitis C’s core protein can induce insulin resistance, steatosis (fatty liver) and diabetes.⁷

On the other hand, steatosis predisposes to diabetes. Scores on the Fatty Liver Index (FLI) range from 0 to 100 and are equivalent to the percentage chance of having a fatty liver.

Among people who do not drink excessive amounts of alcohol, after adjusting for potential confounding factors, a FLI >70 increases the risk of developing diabetes over the next nine years five-fold in men and more than 20-fold in women compared with those with a FLI <20.³

 

Consequences
Despite a relatively benign reputation,⁴ NAFLD is associated with considerable morbidity and mortality. For example, after adjusting for age and sex, patients with type 2 diabetes and NAFLD are more likely to develop non-proliferative or proliferative retinopathy and CKD than those without NAFLD. Indeed, NAFLD doubles the risk of developing CKD and proliferative retinopathy independently of other factors such as BMI, waist circumference, hypertension, diabetes duration, HbA1c and medication.⁸

After adjusting for confounders, NAFLD also roughly doubles cardiovascular disease (CVD) risk in patients with type 2 diabetes.⁹ Adjusting for
the metabolic syndrome (which also increases NAFLD risk5) reduces the strength of the association, but the risk arising from NAFLD is 50 per cent higher than among patients with type 2 diabetes alone.⁹

As mentioned above, NASH can progress to cirrhosis and cancer. Fibrosis progresses in 26-37 per cent of NASH patients, while up to 9 per cent develop cirrhosis within around five years. Another 18-29 per cent of NASH patients show improved histology, with the disease remained stable in the remainder.

BMI and diabetes increase the risk that fibrosis will progress and 4-27 per cent of cases of NASH eventually transform into HCC. Diabetes increases HCC risk between 1.86-fold and four-fold.⁵

Implications for pharmacists
Detecting and treating NAFLD presents problems. For example, NASH often produces few or no symptoms, especially during the early stages. Patients with advanced NASH or cirrhosis may report fatigue, weight loss and weakness.

Cirrhosis can also cause fluid retention, muscle wasting, gastrointestinal bleeding and liver failure.10 Elevations in liver tests, such as alanine aminotransferase (ALT) or aspartate aminotransferase (AST), may raise a suspicion of NASH.¹⁰ However, NASH may also develop without altering liver transaminases.

Currently, a liver biopsy is necessary for a definitive diagnosis, although new imaging methods and biomarkers may reduce the need for invasive procedures in the future.¹

As around 70 per cent of type 2 diabetes patients show fatty livers,¹ it may be reasonable to assume that a patient has NAFLD until proven otherwise. Pharmacists could suggest that patients raise the issue with their diabetologist or GP.

Currently, there are no proven treatments for NASH and lifestyle modification remains the gold-standard approach to management.¹ However, some interventions already used to treat obesity and type 2 diabetes may help.

For example, in people with NAFLD or NASH, weight-loss decreases hepatic steatosis and liver transaminases, as well as modestly improving necrosis, inflammation and fibrosis.

Reducing visceral fat seems to be a particularly important intervention, as it is a strong risk factor for hepatic steatosis, inflammation and fibrosis.¹ While agents such as orlistat help reduce BMI, they seem to have no additional benefit in NAFLD or NASH compared to weight loss alone.¹ Many obese people and those with type 2 diabetes take statins as primary or secondary prevention. In patients with diabetes, statins may reduce HCC risk by 25-40 per cent. Future studies are needed to confirm these results.⁵

Some oral antihyperglycaemic drugs may improve NASH, including dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inactivates glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion and inhibits glucagon production.

So, blocking GLP-1 improves glycaemic control. However, DPP-4 metabolises several other substrates, including several chemokines implicated in NASH pathogenesis.

DPP-4 may also mediate fibrogenesis. Indeed, NASH patients show increased levels of serum DPP-4 compared to controls.

Furthermore, DPP-4 levels in the liver correlates positively with the severity of hepatic steatosis. Animal studies suggest that linagliptin, a DPP-4 inhibitor currently in phase III trials, reduces hepatic fat accumulation.⁴

Finally, hepatic disease can also influence the choice of antihyperglycaemic drug. For example, patients with hepatic impairment – including pre-treatment ALT or AST greater than three times the upper limit of normal (ULN) – should not receive vildagliptin¹¹ or Eucreas (vildagliptin and metformin). Pharmacists need to be familiar with hepatic restrictions on drugs taken by type 2 diabetes patients.

Liver disease is both a cause and consequence of diabetes. NASH, for example, markedly increases the risk of complications, including CKD, retinopathy and HCC. Early detection and treatment is important to try to interrupt progression,¹ although many patients are asymptomatic and liver enzymes may be normal.

Weight loss and several drugs used in type 2 diabetes management may attenuate the risk, although more research is needed. Pharmacists also need to remain cognisant of the impact of liver impairment on treatment choice.

Liver diseases are an under-appreciated complication of diabetes and obesity, but healthcare professionals should not underestimate their influence on morbidity and mortality.

Mark Greener, a former research pharmacologist, is a freelance writer on health-related issues.

Non-alcoholic fatty liver disease – what you need to do

 

Non-alcoholic fatty liver disease (NAFLD)
NAFLD is indicated by more than 5 per cent liver fat in the absence of other identifiable causes. Due to its high prevalence, NAFLD should always be suspected in patients with type 2 diabetes. Patients should be advised to discuss the condition with their GP or diabetes specialist, as it increases the risk of several complications.

 

Non-alcoholic steatohepatitis (NASH)
Characterised by fat in the liver along with inflammation and damage, NASH often has few symptoms. It may be indicated by elevated liver test readings, but this is not guaranteed. There are no confirmed treatments for NASH, and patients should be given lifestyle advice, focusing on reducing visceral fat. Drugs such as orlistat have shown no additional benefit in treating the condition compared with weight loss alone.

 

Hepatocellular carcinoma (HCC)
The majority of liver cancers are caused by HCC, which develops in about 0.5 per cent of patients with NASH in seven years. HCC has a poor prognosis as around 80-90 per cent of lesions cannot be removed completely by surgery, and HCC is usually fatal within six months. Prevention by changing lifestyle choices to reduce risk is the main focus of treatment, although statins may reduce the risk of developing HCC by 25-40 per cent.

 

Key facts about non-alcoholic fatty liver disease

• Around 70 per cent of patients with diabetes have NAFLD, while 30-70 per cent of patients with hepatitis C are affected.

• Between 20 and 30 per cent of patients with NAFLD will go on to develop NASH.

• About one in 200 patients with NASH will develop liver cancer in seven years.

• Patients with type 2 diabetes and NAFLD are at double the risk of a host of conditions, including CVD, CKD and proliferative retinopathy.

Reflect
What are the symptoms of NAFLD? What is the risk of hepatocellular carcinoma for patients with non-alcoholic steatohepatitis? Which antihyperglycaemic drugs have been shown to benefit NASH and reduce hepatic inflammation?

Plan
This article discusses non-alcoholic fatty liver disease and its link with type 2 diabetes. It details how fatty livers can be a cause and a consequence of diabetes, the progression to cirrhosis and hepatocellular cancer as well as implications for pharmacists.

Act

• Find out more about NAFLD including information that might help you explain the condition to patients from the Patient UK website at

• http://tinyurl.com/ NAFLD01 and http://tinyurl.com/NAFLD02.

• Read more about cirrhosis and its symptoms and diagnosis from the British Liver trust website at http://tinyurl.com/NAFLD03.

• Find out more about hepatocellular cancer from the Cancer Research UK website at http://tinyurl.com/NAFLD04.

• Revise your knowledge of retinopathy, of which the risk is increased with NAFLD, from the RNIB website at http://tinyurl.com/NAFLD05.

Evaluate

 Are you now confident in your knowledge of NAFLD and its link with diabetes? Are you familiar with the conditions that NAFLD can progress to such as cirrhosis and cancer?

 

References

1. Cusi K Nonalcoholic fatty liver disease in type 2 diabetes mellitus Curr Opin Endocrinol Diabetes Obes 2009;16:141-9

2. Zhou XH, Qiao Q, Zethelius B et al. Diabetes, prediabetes and cancer mortality. Diabetologia 2010;53:1867-76

3. Balkau B, Lange C, Vol S et al. Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study. BMC Gastroenterol 2010;10:56

4. Schuppan D, Gorrell MD, Klein T et al. The challenge of developing novel pharmacological therapies for non-alcoholic steatohepatitis. Liver Int 2010;30:795-808

5. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51:1820-32

6. Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis 2010;42 Suppl 3:S206-14

7. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA et al. Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol 2009;15:280-8

8. Targher G, Bertolini L, Rodella S et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008;51:444-50

9. Targher G, Bertolini L, Poli F et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005;54:3541-6

10. de Marco R, Locatelli F, Zoppini G et al. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 1999;22:756-61

11. Galvus Summary of Product Characteristics http://www.medicines.org.uk/emc/medicine/20734 accessed 25 September 2010

 

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