NASH or Nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is inflammation and damage of the liver caused due to the deposition of fat in the liver.

Read more about Liver Anatomy, Structure and Function

NASH is part of a group of conditions called nonalcoholic fatty liver disease (NAFLD) which means simply deposition of fat in the liver. Most of the patients of NAFLD have no signs or symptoms of the disease. Once NAFLD gets associated with inflammation and liver damage, it is called NASH.

NASH can lead to fibrosis or scarring of the liver which is a potentially life-threatening condition called cirrhosis. NAFLD is less dangerous than NASH and usually does not progress to NASH or liver cirrhosis.

Most people with NASH are between the ages of 40 and 60 years. It is more common in women than in men. NASH may also have no symptoms in the early stages of the disease.

Stages of NASH, progressing from healthy to steatosis (fat accumulation), inflammation, fibrosis, and cirrhosis
Image Credit: wikipedia

Causes and Risk Factors of NASH

The causes of NAFLD and NASH are multifactorial and are influenced by both environmental and genetic factors. These include:

Being overweight or obese
Diabetes
High cholesterol
High triglycerides
Hypertension
Metabolic syndrome
Polycystic ovary syndrome
Sleep apnea
Underactive thyroid (hypothyroidism)
Underactive pituitary gland (hypopituitarism)

However NASH can also occur in people who have none of these risk factors.

Clinical Features

The disease may be asymptomatic in the early stages. It may take many years for the disease to become severe enough to cause symptoms.

Common symptoms include the following:

Fatigue
Generalized weakness
Unexplained weight loss
Upper abdominal pain or discomfort

As the disease progresses and the liver damage becomes more pronounced, additional symptoms may appear depending on the stage and presentation of the disease.

Jaundice (yellowish discoloration of skin and eyes)
Nausea
Vomiting
Loss of appetite
Diarrhea

Other symptoms may be present

Dark-colored urine
Pale or gray-colored stools
Pruritus or itchy skin
Skin rashes (including acne)
Myalgia
Joint pains
Cushingoid features – Facial swelling and weight due to increased cortisol levels
Hirsutism
Amenorrhea (absence of menstrual periods in women)
Chest pain due to pleuritis
Abnormal blood vessels on the skin (spider angiomas)
Abdominal distention (swelling)
Hepatic encephalopathy (loss of brain function-mental confusion, drowsiness, slurring of speech)
Ascites (fluid in the abdomen)
Swelling of the legs (edema)
Easy bruising and bleeding.
Splenomegaly
Hepatomegaly

Diagnosis

For making a diagnosis, complete physical examination and medical history of the patient are taken into consideration.

The presence of fatty liver in the absence of other factors that are commonly responsible for liver fat accumulation is the defining criteria for NASH. Common such factors include excessive alcohol intake, drug-induced steatosis, viral hepatitis, etc. In the presence of any of these factors, the diagnosis of NASH is unlikely.

If NAFLD or NASH are suspected, the following tests are carried out to confirm the diagnosis as well as to assess liver damage.

Liver function tests (LFTs)

Serum aminotransferases (ALT- alanine aminotransferase and AST – aspartate aminotransferase)

Liver damage due to inflammation causes the level of these enzymes to be elevated. However, some people with NAFLD or even NASH may have a normal level of liver enzymes.

Unlike in alcoholic liver disease, the ratio of AST / ALT in NASH is usually < 1.

Alkaline phosphatase and gamma-glutamyl transpeptidase (GGT)

Levels may be increased.

Hyperbilirubinemia, hypoalbuminemia, and prolongation of prothrombin time (PT) or INR may be seen in severe cases of liver damage.

Read more about Liver Function Tests or LFTs

Imaging tests

Ultrasound
Computed Tomography or CAT scan
Magnetic resonance imaging or MRI

These tests help to identify fat accumulation in the liver. But they can’t distinguish between simple fatty liver or NASH since they can’t show inflammation or fibrosis.

Imaging tests to measure liver fibrosis or scarring

Transient elastography

A special ultrasound machine or FibroScan is used. Similar to ultrasound, it is a painless and non-invasive test.

Magnetic resonance elastography (MRE)

It is a newer and noninvasive test that can show gradients of fibrosis and scarring throughout the liver. It is a more reliable measure of liver fibrosis in severely obese patients.

MR-EFF (elastography fat fraction) is used to determine the percentage of fat and scarring present.

Liver biopsy

During this procedure, a needle is used to remove a small piece of tissue from the liver, which is then examined under a microscope.

Multiple features identified on microscopy lead to a diagnosis of nonalcoholic steatohepatitis. These include steatosis, ballooning degeneration, and lobular inflammation.

Steatosis is predominantly macrovesicular, with lobular inflammation and ballooned hepatocytes in zone 3.

Liver cell damage seen as ballooned hepatocytes is an important finding in NASH and helps to distinguish the progressive disease from less aggressive forms. The cytoplasm may contain Mallory-Denk bodies which are clumped dense eosinophilic material.

Portal inflammation is usually minimal to mild in adult patients while it is more pronounced in children. Also, the portal inflammation is seen more commonly in progressive forms of the disease.

Over a period of time, fibrosis develops, initially in the centrilobular zone (zone 3) as chicken wire fibrosis. Later there occurs portal-central bridging fibrosis and cirrhosis.

Lipid profile

To determine the blood levels of cholesterol and triglycerides.

Blood sugar level

This may include fasting blood sugar, postprandial blood sugar, or random blood sugar.

HBA1C

This test determines the average amount of blood sugar present in the body over the past 3 months.

Glucose present in the blood attaches to part of the red blood cells. This test measures that part of the red blood cells. It is also called glycated hemoglobin test.

People who have diabetes should get this test regularly to see how well they are able to control their blood sugar levels.

Tests to rule out other causes of fatty liver

Tests for chronic viral hepatitis, like hepatitis B and C
Ceruloplasmin level: to rule out Wilson disease
Alpha 1-antitrypsin levels: to rule out alpha1-antitrypsin deficiency
Serum ferritin: to rule out hemochromatosis

Treatment

Treatment for NASH focuses on managing conditions that increase the risk of NASH.

There is no medicinal treatment for patients with NAFLD or NASH. However, lifestyle changes can halt disease progression. This includes maintaining a healthy weight, eating a healthy diet, exercising regularly, and treating the underlying conditions such as diabetes or hypothyroidism.

It is important to maintain a healthy weight. Loss of excess weight can help to reduce liver fat and associated inflammation, and fibrosis. Obese or overweight persons should aim to lose around 7 to 10 percent of their body weight over a period of one year. This weight loss should be gradual and not rapid as rapid weight loss through fasting can make the condition worse.

Keep your blood sugar within the normal range. People with diabetes should control their sugar levels by diet, exercise, or by blood sugar reducing medicines.

Reduce the total cholesterol and triglyceride levels by eating a healthy diet and exercising regularly. A healthy diet means a balanced diet rich in all the nutrients and must include fresh fruits and vegetables along with whole grains. Foods having a high-fat content or high saturated fats should be avoided.

Avoid consuming excessive alcohol as it can aggravate the condition.

Don’t consume any medicine without consulting your doctor as some of them may harm the liver.

Don’t take dietary supplements blindly or for long periods. Certain vitamins and minerals like vitamins A or iron can be harmful to the liver if consumed in very large quantities.

Be cautious about taking any herbal medicines without the prescription of a qualified practitioner. Some of these contain high levels of toxic chemicals or heavy metals which may be harmful to the liver.

Get vaccinated for hepatitis A and hepatitis B as these viral infections can further cause damage to the liver.

If cirrhosis develops due to NASH, liver transplantation may be considered.

As of now, no drugs have been approved by the FDA for the treatment of NAFLD or NASH. A few drugs are being studied and have shown promising results.

Complications of Nonalcoholic steatohepatitis

Fibrosis and cirrhosis of the liver
Liver failure
Complications due to chronic liver disease (increased blood pressure in the portal vein, esophageal varices, gastrointestinal bleeding, ascites, etc)
Liver cancer
Cardiovascular disease and Type 2 diabetes.**

**Association of NASH and NAFLD with cardiovascular disease and type 2 diabetes is bidirectional.

Patients of cardiovascular disease and Type 2 diabetes are at an increased risk of developing NASH and NAFLD. Inverse also holds true.

Prognosis

Prognosis depends on the degree of fibrosis and liver scarring. About 10% of patients with NAFLD progress to cirrhosis over a period of 20 years.

Consumption of alcohol, liver-damaging drugs, and metabolic disorders all lead to an acceleration of the disease and must be completely avoided.

In the absence of complications, the prognosis is good. Complications like chronic hepatitis, liver failure worsen the prognosis. NAFLD and NASH patients are also at an increased risk of developing liver cancer or heart diseases.

References

Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917-923
Dixon JB, O’Brien PE, Bhatal PS. A wider view on diagnostic criteria of nonalcoholic steatohepatitis (reply). Gastroenterology 2002;122:841-842
Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002;35:367-372
Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis—an expanded clinical entity. Gastroenterology 1994;107:1103-1109

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NASH or Nonalcoholic steatohepatitis

Causes and Risk Factors of NASH

Clinical Features