Need to review the Ped Annals article from which this was drawn to increase accreditation.
Part IV Section 7-D
Non-Alcoholic Fatty Liver Disease (NAFLD --Also known as Non-Alcoholic Steato-Hepatitis (NASH)
Desiree Seeyave, MD
Marcos Alfie, MD
William Treem, MD
SUNY Downstate Medical Center
Brooklyn, NY Draft
Pretest Questions
Q1. Non-alcoholic fatty liver disease (NAFLD) is present in what percentage of obese children?
A. 5%
B. 10%
C. 15%
D. 20%
E. Uncertain
Q2. NAFLD is usually asymptomatic in children. (True or False)
Q3. Cirrhosis of the liver occurs more often in children with Non Alcoholic Steato-hepatitis (NASH) than in adults with same disorder (True or False)
Q4. NAFLD in childhood often associated with:
A. Type 2 DM
B. Rheumatoid arthritis
C. Hypothyroidism
D. All of the above
Q5. NAFLD usually responds to weight reduction. (True or False)
Q6. The most accurate way to diagnosis NAFLD and NASH is:
A. Elevated transaminases
B. Liver biopsy
C. Splenomegaly
D. Abdominal ultrasound
Learning Objectives:
At the conclusion of this section, residents and physicians will able to:
1. Appreciate the pathophysiology of non-alcoholic fatty liver diseases (NAFLD and NASH)
2. Distinguish NAFLD from other causes for fatty liver in childhood.
3. Identify the nutritional consequences of NAFLD and these other causes.
4. Develop a diagnostic approach to a child suspected of having NAFLD, NASH or these other causes.
5. Know when and how to treat NAFLD and these other causes, and
6. When to refer a child to a Pediatric Gastrointestinal specialist
Facilitator Preparation
The module is derived in part from:
Alfie ME and Treem. Non-Alcoholic Fatty Liver Disease. Pediatric Annals. 2006 2006 Apr;35(4):290-4/297-9.
See also,:
1. Jonas MM. Nonalcoholic fatty liver disease MD, Adolescent Medicine Clinics, 2004 Feb;15(1):159-73
2. McCullough AJ
* The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clinics in Liver Disease. 2004; 8(3):521-33,
* Pathophysiology of nonalcoholic steatohepatitis.J Clin Gastroenterol. 2006 Mar;40(3 Suppl 1):S17-29.
Introduction
Non-alcoholic fatty liver (NAFLD) is defined as fatty infiltration of the liver in the absence of any known causative factor. NAFLD was first described in obese, diabetic females, with no history of alcohol ingestion, who had hepatic histology that was consistent with alcoholic hepatitis.
NAFLD is usually asymptomatic but is most often associated with obesity -- a Body Mass index (BMI) > 95th% for age. With the rising prevalence of obesity in children, NAFLD has been increasingly recognized in children, and may be the most common form of chronic liver disease in the pediatric age group. As many as 10% of obese children have NAFLD, and many of these - percentage as yet unknown - will go on to have cirrhosis. It is sometimes manifested as a modestly enlarged liver on a routine physical examination of an overweight child. A liver biopsy, however, is necessary to make a firm diagnosis.
A Case Study - Part I
Oliver B is a 10-year-old boy, born to Haitian parents and who has lived in Brooklyn all his life. He is currently in 5th grade and is developmentally appropriate. His diet consists of 'fast food' at least 3 times a week, chips, lots of juice and soda. He plays video games everyday after school and plays no sports. You notice that his mother weighs about 200lbs and his father has a history of type 2 diabetes and hypertension, and his maternal grandmother died of a heart attack at age 55. He is brought to your practice for routine follow up - his last visit was 1 year ago, at which time his weight was in the 95th percentile. At this visit, his weight and height are above the 95th percentile and his BMI is 30 (>95th percentile). Physical examination is significant for obesity, acanthosis nigricans behind his neck and a non-tender 1-2 cm palpable liver.
Q1. What is the pathophysiology of NAFLD?
A1. The pathogenesis of NAFLD is not completely known. When the rate of lipogenesis exceeds that of lipolysis, fat is deposited in the liver. Hepatic steatosis may occur in obesity, acute starvation, excessive dietary intake of fat and total parenteral nutrition. Another explanation for fat deposition is the decreased use of fatty acids in the liver by disturbed mitochondrial oxidation or decreased synthesis of lipoproteins.
Insulin resistance is an important component in the pathogenesis of NAFLD, and elevated insulin levels have been found in children and adults with NAFLD, even without obesity or hyperglycemia. The normal action of insulin is to retain triglycerides in the liver; high insulin levels block mitochondrial fatty acid oxidation, thus insulin resistance leads to fat accumulation in hepatocytes.
Tumor necrosis factor-alpha (TNF-alpha) also plays a role in the development of NAFLD. This is a proinflammatory cytokine that releases reactive oxygen species from mitochondria, resulting in cell injury and death. TNF-alpha expression in adipose tissue is very elevated in obesity and hyperinsulinemia, and its effects are thought to be related to insulin resistance.
Many authors refer to the first and second hit theory in the development of NAFLD and NASH. The first component or "first hit is the accumulation of triglycerides in hepatocytes. A "second hit" is then required to cause progression to hepatocellular injury, with inflammation and fibrosis, (see below).
Schematic representation of the pathogenesis of hepatic steatosis.
Insulin resistance causes accumulation of free fatty acids in hepatocytes, the "first hit" of hepatic steatosis. A "second hit" injury mediated through oxidative stress and lipid peroxidation via hepatic cytochrome P450 system causes release of inflammatory cytokines, leading to inflammation and cell necrosis. The result is fibrogenesis and steatohepatitis.
TEACHING CAPTION: NAFLD is caused by a 'first hit' of fat accumulation in the liver. Excessive dietary intake of calories, especially fat and carbohydrate (particularly refined sugars like sucrose and fructose), coupled with lack of physical exercise causes more rapid progression of obesity and fatty infiltration = Non Alcoholic Fatty Liver Disease = NAFLD. A 'second hit' by inflammatory mediators contributes to hepatic inflammation and fibrosis, and progression to Non Alcoholic Steatohepatitis = NASH.
TABLE 1: Definitions
Genetic factors may play a role in promoting fatty liver and in promoting progression to steatohepatitis. These genes include those that regulate body weight through leptin and adiponectin; genes that control P-450 regulation and generation of oxygen free-radicals, alcohol metabolism, anti-oxidant defenses via hepatic glutathione and vitamin E, Beta-carotene and Vitamin C. Also heterozygotes for hereditary hemochromatosis and alpha-1-antitrypsin deficiency seem predisposed to NASH.
Q2. What are the histologic features of NAFLD and NASH?
A2. NAFLD is characterized by the build up of fatty macrovesicles in the parenchymal cells of the liver in the absence of significant alcohol ingestion, and is often associated with a number of underlying disorders (see Table 1). NAFLD is a spectrum of severity of macrovesicular steatohepatitis, the accumulation of large lipid droplets that displace and condense the nuclei of hepatocytes, with varying degrees of inflammation and fibrosis.
Without inflammation, NAFLD may be a benign, reversible condition. With inflammation, the condition is called non-alcoholic steatohepatitis. It is thought that repeated episodes of inflammation cause progression to chronic liver disease with significant fibrosis and cirrhosis. Features of NASH include macrovesicular steatosis, pericellular/sinusoidal fibrosis, parenchymal inflammation with lymphocyte-predominance, and ballooning degeneration (Fig. I)
TEACHING CAPTION: Since NAFLD is a histologic diagnosis, it can only definitively be made by liver biopsy. Laboratory tests including elevated transaminases, and ultrasonography are suggestive of NAFLD but are inadequate for diagnosis.
Q3. What are the clinical features of NAFLD?
A3. NAFLD and NASH are usually asymptomatic. Symptoms, if present, are more common in adolescents than younger children. Clinical features include:
Table 2. Signs and symptoms of NAFLD/NASH
- Fatigue.
- Malaise.
- Vague right-upper-quadrant abdominal pain.
- Hepatomegaly - may be difficult to appreciate due to abdominal wall fat.
- Acanthosis nigricans, (brown, velvety, hyperkeratotic plaques) is commonly found on the back of the neck and in the axillae of children and adolescents with insulin resistance.
- Abnormal ALT (discovered on routine testing).
TEACHING CAPTION: NAFLD is usually found incidentally by abnormal LFT's or enlarged liver on examination or CT or US, but it should be kept in mind when treating any obese child or adolescent.
A Case Study - Part 2
You suspect that Oliver B may have NAFLD. You explain this to his mother, and point out that with his sedentary lifestyle, intake of high-calorie foods and family history of obesity, hypertension, diabetes and heart disease, he is also at risk of these life-style diseases.
What diagnostic tests would you perform next?
Given the basic information, residents should be able to create a differential on their own. Stop. Let them develop a list of possibilities and a set of laboratory or other diagnostic tests to confirm or rule out causes for the signs and symptoms listed in Table 2, above.
Q4. What are the laboratory and radiological features of NAFLD?
A4. Laboratory findings in NAFLD and NASH are non-specific.
- LFTS: Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels may be increased two to fivefold, with AST:ALT ratio < 1 (it is the opposite in alcohol-related liver disease.) Gamma-glutamyl transpeptidase (GGT) levels may also be elevated.Other abnormalities of liver function such as decreased albumin and prolonged PT occur only in the very latest stages of liver disease.
- Sonogram: a granular-appearing, echogenic liver that is difficult to penetrate with NAFLD, but it may be normal if the degree of steatosis is less than 30%. This is the most practical method of determining an enlarged fatty liver.
- CT scan: performed in patients with chronic abdominal pain, can indicate the presence of fatty infiltration of the liver.
- MRI: may show fatty liver, but is not good for detecting inflammation and fibrosis
- Liver biopsy: remains the gold standard for making the diagnosis of NAFLD/NASH since it is a histologic diagnosis. Findings on biopsy include: greater than 5% lipid-filled hepatocytes with nuclei compressed to the periphery of the hepatocytes, ballooned hepatocytes, periportal inflammatory cells and bridging fibrosis.
A Case Study - Part 3
Oliver B's LFT results are as follows:
Total protein 6.3 AST 100
Albumin 4 ALT 100
Total bilirubin 0.9 LDH 200
Alkaline Phosphatase 500
His mother is concerned about the diagnosis of NAFLD. She asks you if there are any other causes of enlarged fatty liver in children. What do you tell her?
Q5. What are other causes for fatty liver in childhood? (Repeat suggestion about creating a differential)
A5. NAFLD and NASH may be associated with or caused by a variety of underlying diseases or drugs
Table 3. Causes of NAFLD/NASH
................................................................................................
Acquired metabolic conditions
Obesity
Diabetes mellitus
Rapid weight loss
Total parenteral nutrition
Acute starvation
Genetic metabolic conditions
Wilson's disease
Hereditary tyrosinemia
Abeta/hypobeta lipoprotenemia
Surgical procedures
Jejunoileal bypass
Gastroplasty
Extensive small bowel resection
Bilio-pancreatic diversion
Drugs/toxins
Glucocorticoids
Amiodarone
Estrogens
Isoniazid
Nifedipine
Others
Miscellaneous
Small bowel bacterial overgrowth
Small bowel diverticulosis
Weber-Christian disease
..................................................................................................
TEACHING CAPTION: The most common association with NAFLD is obesity, often found with comorbidities of obesity including diabetes mellitus. Obesity, however, is not the only cause for NAFLD/NASH
NAFLD is a diagnosis of exclusion, and other causes of enlarged fatty liver or abnormal LFT's must be considered in the work-up of children.
When there is an abnormal ALT coupled with radiographic and histologic evidence of fatty liver and hepatitis, other causes must be excluded. These include alcohol abuse and viral, genetic, autoimmune and drug-induced liver diseases. Hepatitis C must be excluded since it is associated with hepatic steatosis.
The amount of alcohol ingestion required to produce liver disease is questionable, but studies suggest that hepatotoxicity may be caused by 20 g/d in women and 30 g/d in men. Although alcoholism is not as great a problem in pediatrics as it is in adult medicine, alcohol is the most frequent drug of abuse among teenagers.
Alcohol intake may be denied or under-reported, is often hidden from family members and its use may be missed altogether unless it is specifically asked by the clinician. Alcoholism has to be considered in targeted pediatric populations whenever such patients are found to have evidence of fatty liver.
Q6. What is the Prevalence and risk factors for NAFLD?
A6. Since most individuals with NAFLD are asymptomatic, its prevalence is unknown. Rates of 20% for NAFLD and 2-3% for NASH were found in autopsy studies and in general adult populations.
Abnormal ALT is found in 10-25% of children referred to obesity programs; fatty liver is found in approximately 50% of these patients on sonogram.
The prevalence of these patients who actually have NAFLD or NASH is not known since liver biopsies are not routinely done for abnormal ALT values, but it is estimated that 10% of obese children have NAFLD.
In adults, the risk factors for progression to NAFLD include obesity, type 2 diabetes mellitus, hyperlipidemia, and female gender. The presence of obesity or type 2 diabetes is the strongest predictor of progression of NASH to fibrosis and cirrhosis; other risk factors include age >45, hypertension, AST/ALT ratio > 0.8, hypertriglyceridemia and high insulin resistance.
The risk factors in pediatric patients include overweight (BMI > 85th% for age) or obesity (BMI > 95th% for age), insulin resistance and male gender (2:1 ratio). Obese Hispanic children are more prone to NAFLD than obese Black children, who are least susceptible. Prevalence of NAFLD is expected to increase with the current epidemic of obesity and type 2 diabetes in children.
Q7. What treatment modalities are suggested for obesity associated NAFLD and NASH?
A7. Obese children with NAFLD are treated exactly as those without an enlarged, fatty or inflamed liver. Issues of treatment are found in the obesity cycle [hyperlink] Of note, the enlarged fatty liver regresses in size and fat content with effective weight loss.
Control of obesity, type 2 diabetes, blood pressure and lipids are important to prevent progression of NAFLD to NASH, and NASH to cirrhosis of the liver and liver failure.
[Approaches to obesity treatment at different ages are provided in Part III of the Teacher's Guide.]
Q8. When is it necessary to refer to a pediatric gastroenterologist?
A8. The general pediatrician is responsible for a complete preliminary work-up to reveal any comorbidities to the obesity or other causes for an enlarged liver. Children with poorly controlled Diabetes, for example, can develop the Mauriac Syndrome with a glycogen filled liver. [Maher et al, 2007]
Once that is done, the gastroenterologist will be the only one who can make a definitive diagnosis by needle biopsy. If the diagnosis is NAFLD without inflammation or cirrhosis (not NASH), the child will return to care of the general pediatric team for weight reduction. If, however, there is evidence of NASH, the gastroenterologist will become part of the team delivered care.
References
Alfie ME and Treem. Non-Alcoholic Fatty Liver Disease. Pediatric Annals. 2006 2006 Apr;35(4):290-4/297-9.
Jonas MM. Nonalcoholic fatty liver disease MD, Adolescent Medicine
Clinics, 2004 Feb;15(1):159-73.
Mahesh S, Karp RJ, Castells S, Quintos JB. A three year old boy with Mauriac syndrome. Endocrine Practice. 2007;13(1):63-66.
McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clinics in Liver Disease. 2004; 8(3):521-33,
McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis.J Clin
Gastroenterol. 2006 Mar;40(3 Suppl 1):S17-29.
Annotated Answers:
A1. The Answer is B; The present estimate of occurrence is 10%. Much depends, however, on how the disorder is defined. A looser definition (just an enlarged liver) would lead to a higher percentage.
A2. The Answer is True; Fatty liver is by and large a clinically asymptomatic disorder.
A3. The Answer is False; Unfortunately, children and adolescents have longer time to experience the hepatic dysfunction and its consequences than does an adult.
A4. The Answer is A; Truncal obesity in childhood is one component of the (dys)metabolic syndrome and is a cause and consequence of insulin resistance. Type 2 Diabetes Mellitus is another component with the same origins. Neither RA or hypothyroidism is associated with NAFLD.
A5. The Answer is True; Fortunately, the fatty liver will recede with improved BMI and less insulin resistance at least prior to cirrhosis.
A6. The Answer is B; A definitive diagnosis requires a liver biopsy. Transient elevations in transaminase levels, splenomegaly or an enlarged liver on ultrasound are not sufficient to make this diagnosis
