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![Clinical features of AFLD
Clinical features Pathology Typical disease course
Alcohol-associated steatosis
•Usually asymptomatic
•Some patients report a sensation of
pressure in the upper abdominal area.
•In some cases, hepatomegaly: soft
consistency
•Accumulation of lipid droplets
in hepatocytes with gradual single-
cell necrosis within the lobules
•May be reversible after cessation
of alcohol consumption
•Acute exacerbation and risk of
hepatic failure are rare.
•May progress to alcohol-associated
steatohepatitis and liver
fibrosis if alcohol consumption
continues
Alcohol-associated hepatitis [3]
•Acute jaundice
•Fever
•Tender hepatomegaly
•Malaise
•Nausea, anorexia
As discussed before
•Reversible in mild cases
•Progression of liver fibrosis is
accelerated.
Alcohol-associated cirrhosis [4]
•Final stage of ALD
•Asymptomatic in the early stage
•Fatigue, weight loss, abdominal
distention, spider angiomata
•Decompensated cirrhosis:
bleeding varices, ascites, encephalop
athy, jaundice
•Infiltration of lymphocytes
•Massive accumulation of fat
in hepatocytes
•Formation of fibrous septa
and regenerative nodules
•Perivascular sclerosis of central
veins (especially in the early stage)
•Irreversible
•Liver transplantation is the only
definitive treatment option.](https://image.slidesharecdn.com/fattyliver-251110092758-fa212bb2/75/Fatty-liver-approach-to-fatty-liver-and-management-18-2048.jpg)
Fatty liver: approach to fatty liver and management
- 1. Fatty Liver Done By:Joseph Rishmawi Supervisor: Dr. Ahmad Abuayyash
- 2. Definitions ◤ Steatosis: Accumulationof fat (mainly triglycerides) within liver cells (hepatocytes). ◤ Steatohepatitis: Fat accumulation plus inflammation and hepatocellular injury. ◤ Alcohol-associated steatosis: due to harmful alcohol consumption. ○ Men: ≥ 3 drinks per day or ≥ 21 per week ○ Women: ≥ 2 drinks per day or ≥ 14 per week ◤ Metabolic dysfunction-associated steatotic liver disease (MASLD) ○ A type of steatotic liver disease that occurs in individuals with ≥ 1 criterion for metabolic syndrome in the absence of an alternative cause (e.g., heavy alcohol use) ○ Previously referred to as nonalcoholic fatty liver disease (NAFLD) ◤ Metabolic dysfunction-associated steatohepatitis (MASH) ○ A subtype of MASLD characterized by chronic hepatocellular inflammation and damage ○ Previously referred to as nonalcoholic steatohepatitis (NASH)
- 3. Epidemiology ◤ AFLD: ○ Secondmost common cause of liver cirrhosis in the United States ○ 28% of the US population exceeds the recommended limits of alcohol consumption. ○ Lifetime prevalence of alcohol use disorder: 18% ○ ∼ 10–20% of heavy drinkers develop cirrhosis. ○ In Palestine, direct data on ALD prevalence is scarce ◤ NAFLD: ○ A cross-sectional study conducted in Nablus, Palestine, in 2022, involving 399 T2DM patients, revealed that 49.7% had moderate to severe fatty liver disease (FLD) as diagnosed by ultrasound. This prevalence is notably higher than the global average, which is estimated to be around 55.5% among T2DM patients.
- 4. Etiology ◤ MASLD isa multifactorial disease with metabolic and genetic components. ◤ Cardiometabolic risk factors: any criterion for metabolic syndrome ○ Central obesity ○ Prediabetes or T2DM ○ Hypertension ≥ 130/85 mm Hg or taking antihypertensives ○ Hypertriglyceridemia, low HDL cholesterol , or taking lipid-lowering drugs ◤ Genetic factors: Individuals with a first-degree relative with MASH-related cirrhosis are at increased risk.
- 5. ◤ Criteria formetabolic syndrome: ≥ 3 must be present (i.e., the patient is either diagnosed with or receiving treatment for the condition) ○ Elevated blood glucose: fasting glucose ≥ 100 mg/dL ○ Elevated blood pressure: systolic ≥ 130 mmHg and/or diastolic ≥ 85 mm Hg ○ Elevated triglycerides: ≥ 150 mg/dL ○ Low HDL-C ○ Men: < 40 mg/dL ○ Women: < 50 mg/dL ◤ Abdominal obesity ○ Men: waist circumference ≥ 102 cm or > 40 in ○ Women: waist circumference ≥ 88 cm or > 35 in ◤ Abdominal obesity (i.e., accumulation of fat in visceral tissue) is strongly associated with an atherogenic and hyperglycemic state.
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- 9. ◤ Hepatic degradationof ethanol to acetyl-CoA by alcohol dehydrogenase results in NADH excess (see breakdown of ethanol for more details) → ↑ NADH drives the formation of glycerol 3-phosphate (G3P) from dihydroxyacetone phosphate (DHAP) → ↑ in both G3P and fatty acids causes increased triglyceride synthesis in the liver and accompanying inflammation → steatohepatitis → chronic inflammation leads to hepatic fibrosis and sclerosis → portal hypertension and eventually cirrhosis
- 11.
- 14. ◤ MASLD: excessenergy supply → insulin resistance → ↑ circulating dietary sugars and free fatty acids → ↑ hepatic free fatty acids → ↑ triglyceride synthesis → hepatic steatosis ◤ MASH cirrhosis: oxidative stress, endoplasmic reticulum stress, and inflammasome activation → inflammation and hepatocyte stress and/or death → fibrogenesis → cirrhosis
- 16. Natural history offatty liver
- 17. Liver Cirrhosis ◤ Regenerativenodule, extensive fibrosis
- 18. Clinical features ofAFLD Clinical features Pathology Typical disease course Alcohol-associated steatosis •Usually asymptomatic •Some patients report a sensation of pressure in the upper abdominal area. •In some cases, hepatomegaly: soft consistency •Accumulation of lipid droplets in hepatocytes with gradual single- cell necrosis within the lobules •May be reversible after cessation of alcohol consumption •Acute exacerbation and risk of hepatic failure are rare. •May progress to alcohol-associated steatohepatitis and liver fibrosis if alcohol consumption continues Alcohol-associated hepatitis [3] •Acute jaundice •Fever •Tender hepatomegaly •Malaise •Nausea, anorexia As discussed before •Reversible in mild cases •Progression of liver fibrosis is accelerated. Alcohol-associated cirrhosis [4] •Final stage of ALD •Asymptomatic in the early stage •Fatigue, weight loss, abdominal distention, spider angiomata •Decompensated cirrhosis: bleeding varices, ascites, encephalop athy, jaundice •Infiltration of lymphocytes •Massive accumulation of fat in hepatocytes •Formation of fibrous septa and regenerative nodules •Perivascular sclerosis of central veins (especially in the early stage) •Irreversible •Liver transplantation is the only definitive treatment option.
- 19. Clinical features ofNAFLD ◤ Often asymptomatic ○ MASH can manifest with signs of advanced liver disease, e.g.: ○ Hepatomegaly, splenomegaly ○ Clinical features of cirrhosis
- 20. Diagnosis of AFLD ◤Early ALD ○ Elevated transaminases ○ ↑ ALT and ↑ AST (typically < 400 U/L) ○ AST > ALT ○ ↑ Alkaline phosphatase ○ Macrocytic anemia ○ ↑ Serum ferritin
- 21. Diagnosis of AFLD ◤Clinical diagnosis of alcohol-associated hepatitis ○ Onset of jaundice within the past 8 weeks ○ ≥ 6 months of ongoing alcohol consumption above the threshold and < 60 continuous days of abstinence from alcohol before jaundice onset ◤ Laboratory studies ○ Liver chemistries in alcohol-associated hepatitis ■ AST: > 50 IU/L ■ Both AST and ALT: < 400 IU/L ■ AST:ALT ratio: > 1.5 ■ Total bilirubin: > 3 mg/dL ○ Additional liver studies ■ GGT: > 100 IU/L ■ ALP: ↑ ■ INR: > 1.5 ■ Albumin: < 3 g/dL ○ CBC ■ WBC: > 12,000/mm3 ■ Platelets: ↓ or ↑ ■ Macrocytic anemia (↓ hemoglobin with ↑ MCV) ◤ BMP: to assess for AKI and calculate severity scores
- 22. Imaging ◤ Ultrasound: firstline ○ Mild hepatomegaly ○ Blood vessels cannot be visualized. ○ ↑ Liver echogenicity due to steatosis; may be focal or diffuse ◤ CT: ↓ liver attenuation
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- 26. Liver biopsy ◤ Indications(not routinely recommended) ○ Unclear diagnosis because of the presence of confounding factors (e.g., chronic jaundice) ○ Uncertain alcohol consumption ○ Recruitment to a clinical trial ◤ Technique: Transjugular liver biopsy is preferred. ◤ Findings: signs of alcoholic steatohepatitis and/or cirrhosis
- 27. Diagnosis of NAFLD ◤MASLD is a diagnosis of exclusion. ◤ Rule out alternative causes of hepatic steatosis based on patient history (e.g., current or prior heavy alcohol use), laboratory studies, and imaging. ◤ Consider referral for liver biopsy if the diagnosis remains uncertain. ◤ Normal or ↑ AST and/or ALT ○ AST/ALT ratio usually < 1 ○ AST/ALT ratio of > 1 may indicate progression to cirrhosis. ◤ Normal or ↓ serum albumin ◤ CBC: normal or ↓ platelet count ◤ Tests to rule out alternative diagnoses ○ All patients: serology for hepatitis B and hepatitis C ○ Additional studies based on clinical suspicion
- 28. Screening for fibrosis ◤FIB-4 score ◤ Transient elastography
- 29. Differential diagnosis ◤ Drug-inducedliver injury due to: ○ Amiodarone ○ Methotrexate ○ Tamoxifen ○ Valproate ○ Antiretroviral drugs ○ Corticosteroids ◤ Viral hepatitis ○ Hepatitis C ○ Hepatitis B ◤ Inherited or autoimmune disorders ○ Hemochromatosis ○ Alpha-1 antitrypsin deficiency ○ Wilson disease ○ Autoimmune hepatitis ◤ Reye syndrome ◤ Pregnancy-related conditions ○ HELLP syndrome ○ Acute fatty liver of pregnancy ◤ Nutrition-related conditions ○ Malnutrition ○ Acute weight loss (e.g., from metabolic surgery or starvation) ○ Celiac disease ○ Parenteral nutrition
- 30. Management of AFLD ◤Immediate cessation of alcohol consumption ◤ Multidisciplinary management of AUD ◤ Hepatology referral for individuals with advanced liver fibrosis or cirrhosis ◤ Treatment of alcohol-associated hepatitis and treatment of cirrhosis as indicated ◤ Liver transplant evaluation for patients with severe disease ◤ Pharmacological therapy ○ Glucocorticoids ■ Indication: Severe alcohol-associated hepatitis (i.e., MELD score > 20) and no contraindications ■ Prednisolone ■ Methylprednisolone ○ N-Acetylcysteine ◤ Monitoring: assess response after 4 or 7 days of treatment with glucocorticoids.
- 31. Management of NAFLD ◤Nonpharmacological management ○ Lifestyle changes ○ Healthy diet, e.g., Mediterranean diet ○ Regular exercise ○ Avoidance of alcohol ○ Weight loss for patients who are overweight ◤ Management of associated metabolic conditions ○ Management of diabetes mellitus ○ Management of obesity ○ Management of hypertension ○ Management of ASCVD
- 32. Management ◤ Pharmacological management ◤Consider the following medications in consultation with a specialist (e.g., hepatologist) to reduce hepatic steatosis and/or steatohepatitis: ◤ MASLD ○ SGLT-2 inhibitor (e.g., dapagliflozin or empagliflozin) for patients with T2DM ○ Tirzepatide for patients with T2DM or obesity ◤ MASH ○ Vitamin E for certain patients without T2DM or cirrhosis ○ GLP-1 receptor agonist (e.g., semaglutide or liraglutide) for patients with T2DM or obesity and no cirrhosis ○ Pioglitazone for patients with T2DM ○ Resmetirom for patients with moderate to advanced fibrosis (stages F2-F3)
- 33. Management ◤ Monitoring forliver fibrosis ◤ Reevaluate all patients with MASLD or cardiometabolic risk factors for MASLD for advanced liver fibrosis using noninvasive testing, e.g., the FIB-4 score. ○ Every 1–2 years for patients with either: ○ Prediabetes or T2DM ○ ≥ 2 other cardiometabolic risk factors for MASLD ◤ Every 2–3 years for patients with only one of the following risk factors: ○ Central obesity ○ Hypertension or taking antihypertensive therapy ○ Dyslipidemia or taking lipid-lowering drugs
- 34. Complications ◤ Decompensated cirrhosis ◤Mainly characterized by a constellation of clinical features resulting from decreased hepatic function: ○ Portal hypertension ○ Ascites ○ Hepatic encephalopathy ○ Coagulopathy ○ Hepatorenal syndrome ○ Hyperestrogenism ○ End-stage liver disease
- 35. ◤ Zieve syndrome ◤A rare condition that can occur in individuals with ALD ◤ Characterized by the following triad: ○ Hemolytic anemia ○ Jaundice ○ Hyperlipidemia
- 36. Prognosis ◤ MASLD ○ Lowrisk of progression to cirrhosis or hepatocellular carcinoma in patients with only one cardiometabolic risk factor ○ The risk of progression increases with each additional risk factor. ○ Approximately 20% of patients with MASH develop liver fibrosis.
- 37. Hyperemesis gravidarum ● Severe,persistent nausea and vomiting associated with a > 5% loss of pre-pregnancy weight and ketonuria with no other identifiable cause. ● Risk factors: ○ Multiple gestation ○ Hydatidiform mole ○ Nulliparity ○ Migraine headaches ○ GERD ● Pathophysiology: May be multifactorial, mostly related to increased levels of human chorionic gonadotropin (hCG).
- 38. Hyperemesis gravidarum ● Clinicalfeatures: ○ Nausea, vomiting ○ Physical signs of dehydration ○ Hypersalivation, ○ Orthostatic hypotension ○ Malnourishment ● Diagnosis: ○ Clinical diagnosis (make sure to rule out other causes of nausea and vomiting) ○ Laboratory analysis: Electrolyte disturbances: hypokalemia and hypochloremic metabolic alkalosis or metabolic acidosis (ketoacidosis), Signs of dehydration (e.g., ↑ hematocrit), Ketonuria (due to severe hypoglycemia), elevated serum aminotransferases (suggests more severe disease).
- 39. Hyperemesis gravidarum ● Management: ○Hospital admission ○ IV fluid resuscitation/replacement ○ Lifestyle changes (avoid empty stomach, avoid triggers) ○ Electrolytes and thiamine repletion. ○ Antiemetics, following a stepwise approach: 1. Pyridoxine (vitamin B6) and/or doxylamine 2. For refractory symptoms, add one of the following: Diphenhydramine, Dimenhydrinate, Prochlorperazine, Promethazine 3. For refractory symptoms despite combination therapy above, add one of the following: Metoclopramide, Ondansetron, Promethazine 4. Last resort: Add chlorpromazine or methylprednisolone.
- 40. Hyperemesis gravidarum ● Complications(rare if treated correctly): ○ Maternal: Hypokalemia, Wernicke encephalopathy ○ Fetal: Intrauterine growth restriction, Low birth weight, Preterm birth ● DDx: uncomplicated nausea and vomiting of pregnancy (morning sickness).
- 41. Liver disease ● Intrahepaticcholestasis of pregnancy: ○ Stimulated by estrogen in genetically predisposed women in the second half of pregnancy. Bile acids are incompletely cleared by the liver and accumulate in the plasma. There is a high recurrence rate with subsequent pregnancies. It is the most common liver disease unique to pregnancy. ○ The overall prevalence is 0.5% in North America and Europe. Risk is increased in Chile, Finland, and Sweden, (as is twin pregnancy). ○ Clinical Findings. The most significant symptom is intractable pruritus on the palms and soles of the feet—worse at night—without specific skin findings. ○ Diagnosis: ↑ Total serum bile acid levels (> 10 mcmol/L): confirmatory. ↑ ALT, ↑ AST. Normal or mildly elevated bilirubin. GGT is typically normal. ○ Management. Oral antihistamines for mild cases. Cholestyramine has been used to decrease enterohepatic circulation. First line: ursodeoxycholic acid (reduces bile acid levels and pruritus). Antenatal surveillance at time of diagnosis (viability). Deliver at 36–39 weeks' gestation depending on severity (or at diagnosis if diagnosed at ≥ 37 weeks). ○ Prognosis: The condition is fully reversible postpartum. ○ Complications: Intrauterine fetal demise (1.2% after 37 weeks), Fetal growth restriction, Premature labor and increased preterm birth rates, Meconium-stained amniotic fluid, Neonatal respiratory depression, Recurrence in subsequent pregnancies (60%–90%)
- 42. Liver disease ● AcuteFatty Liver: ○ Rare, life-threatening complication of pregnancy that usually occurs in the third trimester. Prevalence is 1 in 15,000. Maternal mortality rate is 20%. ○ It is thought to be caused by a disordered metabolism of fatty acids by mitochondria in the fetus, caused by deficiency in the long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) enzyme (dysfunction of fatty acid β-oxidation). ○ Risk factors: multiple gestation, BMI? ○ Clinical features: gradual onset, beginning with nonspecific flu-like symptoms (N/V, anorexia…), severe RUQ/epigastric pain with tenderness to palpation, and acute fulminant liver failure (jaundice, fever…), hypertension, proteinuria, edema (mimic PET), acute renal failure (hepatorenal syndrome), pancreatitis, hepatic encephalopathy, coagulopathy (DIC). ○ Diagnosis: ↑ WBC, ↑ AST, ↑ ALT , hyperbilirubinemia, Hyperuricemia, Hypoglycemia, Increased serum ammonia, Coagulopathy (prolonged PT/aPTT), Renal function test: may show acute renal failure. ○ Management. Intensive care unit stabilization with acute IV hydration and monitoring is essential. Prompt delivery is indicated. Resolution follows delivery if the mother survives.
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