NALD, ALD and Cirrhosis

Welcome back to Audioboards. Today, we’re diving into three liver conditions that are incredibly significant: Non-Alcoholic Fatty Liver Disease, Alcoholic Liver Disease, and Cirrhosis.

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Transcript

Welcome back to Audioboards. Today, we’re diving into three liver conditions that are incredibly significant: Non-Alcoholic Fatty Liver Disease, Alcoholic Liver Disease, and Cirrhosis.

Absolutely. Let’s start with the basics. Nonalcoholic fatty liver disease is primarily driven by obesity, diabetes mellitus, and hypertriglyceridemia, often in the context of insulin resistance and metabolic syndrome.

Right, and that’s why there’s been a push to rename it metabolic-associated fatty liver disease—to better reflect its underlying cause. But beyond metabolic syndrome, we also see fatty liver linked to medications like corticosteroids, amiodarone, diltiazem, methotrexate, tamoxifen, irinotecan, oxaliplatin, and even some antiretrovirals.

Exactly. And let’s not forget about environmental and dietary factors—toxins like vinyl chloride, carbon tetrachloride, and yellow phosphorus, as well as high fructose intake, malnutrition, starvation and refeeding syndrome, and even total parenteral nutrition.

It’s fascinating how lifestyle and environment play such a big role. There’s also some data linking it to soft drink and red meat consumption, air pollution exposure, and even prior cholecystectomy. But on the flip side, physical activity is protective.

Let’s talk about the histologic hallmarks which include macrovesicular steatosis, focal polymorphonuclear infiltration, and Mallory hyaline.

And when we think about disease progression, we know that risk factors for advanced fibrosis and cirrhosis include older age, obesity, and diabetes. Interestingly, coffee consumption appears to be protective.

That’s one of my favorite fun facts! But here’s the real concern—patients aren’t just at risk for liver disease. They also have increased risks for cardiovascular disease, chronic kidney disease, and even colorectal cancer.

That’s why we can’t ignore it. And we also need to differentiate it from other causes of fatty liver, like microvesicular steatosis, which we see in Reye syndrome, certain drug toxicities—didanosine, stavudine, linezolid, valproic acid, high-dose tetracycline—and acute fatty liver of pregnancy.

Good point. Now, clinically, most patients are asymptomatic or just have mild right upper quadrant discomfort. Some may have hepatomegaly, but signs of portal hypertension usually indicate advanced fibrosis or cirrhosis.

And when it comes to labs, we typically see mild elevations in aminotransferases and alkaline phosphatase. Unlike alcohol-associated liver disease, the ALT-to-AST ratio is usually greater than 1.0—though that shifts as fibrosis advances.

Another interesting lab clue—some patients have positive ANA or smooth muscle antibodies, plus an elevated ferritin level. And iron deficiency is common, particularly in women, those with obesity, increased waist circumference, diabetes, and among Black and Native American patients.

Now, imaging plays a big role in diagnosis. Ultrasound, CT, and MRI can all demonstrate macrovascular steatosis, but they don’t differentiate simple steatosis from steatohepatitis or fibrosis.

That’s where newer modalities come in. MRI-proton density fat fraction and magnetic resonance spectroscopy allow quantification of hepatic fat and correlate with fibrosis risk. Elastography, whether ultrasound- or MRI-based, helps estimate fibrosis.

Right, and while liver biopsy remains the gold standard, we typically reserve it for cases where noninvasive tests are inconclusive.

Let’s talk about fibrosis assessment. The FIB-4 score is a simple tool that helps rule out advanced fibrosis—it’s based on age, platelet count, AST, and ALT.

Another tool, the NAFLD Fibrosis Score, incorporates additional parameters like BMI, hyperglycemia, albumin, and AST/ALT ratio. For morbidly obese patients, a separate clinical scoring system considers hypertension, type 2 diabetes, sleep apnea, AST, ALT, and race.

And then there’s the Enhanced Liver Fibrosis (ELF) score, which measures tissue inhibitor of metalloproteinase 1, aminoterminal propeptide of type III procollagen, and hyaluronic acid. It correlates well with fibrosis stage and is increasingly used when the FIB-4 score is elevated.

Another option—liver stiffness measurement by elastography. It’s useful when the FIB-4 score suggests possible fibrosis, though accuracy can be lower in obese patients.

So, what’s the treatment approach?

Lifestyle modification is key—weight loss, dietary fructose restriction, fiber intake, and regular exercise. Interestingly, a Mediterranean diet can reduce liver fat even without weight loss!

Yes! Resistance training and aerobic exercise are beneficial, and avoiding alcohol is crucial. As for pharmacologic options, thiazolidinediones improve insulin resistance but cause weight gain.

We also have obeticholic acid, a farnesoid X receptor agonist, and GLP-1 receptor agonists like semaglutide and liraglutide, which have shown promise.

And let’s not forget statins—they may protect against histologic progression. In patients with severe obesity, bariatric surgery can be considered. For those with advanced cirrhosis, liver transplantation is the last resort.

One reassuring thing—fatty liver can have a benign or slowly progressive course and is often reversible with lifestyle changes or by addressing the underlying cause.

True, but in diabetic patients, progression can be more aggressive. And we have to watch for complications like hepatocellular carcinoma, particularly in those with cirrhosis due to NASH.

Now let’s talk about Alcoholic liver disease, which is a critical topic because, while it can be reversible, it remains the leading cause of cirrhosis worldwide.

Right. It is characterized by acute or chronic liver inflammation and parenchymal necrosis induced by alcohol. While it can be reversed with abstinence, it’s often the precursor to cirrhosis.

That’s why early recognition is key. It can present with anything from asymptomatic hepatomegaly to a rapidly fatal acute illness or end-stage cirrhosis.

And in terms of symptoms, patients often report anorexia, nausea, and jaundice. Physical exam may reveal hepatomegaly, abdominal pain, and tenderness. More severe cases can present with splenomegaly, ascites, fever, and even encephalopathy.

Let’s not forget about infection—severe alcohol-associated hepatitis is often complicated by invasive infections, including aspergillosis.

Now, let’s talk about lab findings. In patients with simple steatosis, liver enzymes are often mildly elevated. But the classic pattern we see in ALD, AST is greater than ALT, usually by a factor of two or more.

Exactly. AST is usually elevated but rarely exceeds 400 U/L. We also commonly see macrocytic anemia, leukocytosis with a left shift, and thrombocytopenia.

And if bilirubin levels exceed 10 mg/dL or the prothrombin time is prolonged by 6 seconds or more, that suggests severe alcohol-associated hepatitis. We also frequently see increased transferrin saturation, elevated hepatic iron stores, and sideroblastic anemia in these patients.

Ultrasonography is useful for ruling out biliary obstruction and detecting subclinical ascites. In select cases, C.T with contrast or MRI may be indicated.

And if a liver biopsy is performed, we typically see macrovesicular fat, polymorphonuclear infiltration with hepatic necrosis, Mallory-Denk bodies, and perivenular and perisinusoidal fibrosis.

Differentiating ALD from other conditions is crucial. We always have to consider cholecystitis, cholelithiasis, and drug-induced liver toxicity in the differential.

Right. The history of alcohol use is key in making the correct diagnosis.

Now, let's talk about treatment. Hospital admission is required for patients with hepatic encephalopathy, an INR greater than 1.6, or a total bilirubin of 10 mg/dL or more.

And the number one intervention is abstinence from alcohol. Hospitalized patients should be monitored closely for withdrawal.

To help prevent relapse, we can consider medications like acamprosate, naltrexone, baclofen, topiramate, or gabapentin, in combination with counseling.

Nutritional support is another key aspect—patients are often malnourished, and proper nutrition can improve liver function. Also, avoiding nephrotoxic drugs is essential, especially in severe cases.

Let’s talk about the role of steroids. If the modified Maddrey discriminant function score is 32 or more, or if the MELD score is 20 or greater, we can consider methylprednisolone, 32 mg per day orally, for one month.

Yes, but corticosteroids don’t work for everyone. If the serum bilirubin level fails to decline after 7 days of steroid therapy, that predicts nonresponse and poor survival.

Right, and that’s where scoring models like the Lille model come in—it helps predict steroid responsiveness. The MELD score and the Glasgow Alcohol-Associated Hepatitis Score have also shown better specificity compared to the MDF and Lille scores.

This is why early intervention is critical. Alcohol Liver Disease can be reversible if caught in time, but once cirrhosis develops, the prognosis worsens significantly.

Now let’s dive into cirrhosis, a condition characterized by fibrosis and regenerative nodules in the liver. Causes include chronic viral hepatitis, alcohol, drug toxicity, autoimmune and metabolic liver diseases, and miscellaneous disorders.

That's right. Interestingly, celiac disease appears to be associated with an increased risk of cirrhosis. The disease progresses in three stages: compensated, compensated with varices, and decompensated, which includes ascites, variceal bleeding, encephalopathy, or jaundice.

Let's talk about clinical findings. Symptoms include fatigue, disturbed sleep, muscle cramps, and weight loss. In advanced cirrhosis, patients experience anorexia, nausea, vomiting, and reduced muscle strength. Abdominal pain can result from hepatic enlargement or the presence of ascites. Hormonal abnormalities like menstrual irregularities, erectile dysfunction, and gynecomastia are common.

Absolutely. We also see hematemesis due to variceal bleeding and evidence of vitamin deficiencies. Skin manifestations include spider telangiectasias, palmar erythema, Dupuytren contractures, and Terry nails. Hepato-splenomegaly, Ascites, and jaundice are also frequently observed. Encephalopathy presents with day-night reversal, asterixis, tremor, delirium, and coma.

We can't ignore the hematologic and metabolic complications. Patients may have anemia, thrombocytopenia, or leukopenia. AST and alkaline phosphatase may be mildly elevated, while bilirubin levels progressively increase. There's also hypoalbuminemia and gamma-globulin elevation, similar to autoimmune hepatitis.

Another critical aspect is the increased risk of diabetes mellitus, particularly with HCV, alcoholism, hemochromatosis, and Non Alcoholic fatty liver Disease. Vitamin D deficiency is prevalent. Cardiovascular changes include blunted inotropic and chronotropic responses, QT prolongation, and cirrhotic cardiomyopathy. Relative adrenal insufficiency is also observed.

Moving on to diagnostics, ultrasonography assesses liver size and detects ascites, hepatic nodules, or hepatocellular carcinoma. A liver biopsy confirms fibrosis with regenerative nodules. Endoscopy identifies varices and GI bleeding sources. Wedged hepatic vein pressure measurements can confirm portal hypertension.

The most common causes of cirrhosis include alcohol, hepatitis C, Non Alcoholic fatty liver Disease, and hepatitis B. Hemochromatosis is the most frequent genetic cause, while Wilson disease, alpha-1-antitrypsin deficiency, and celiac disease are other contributors. PBC and secondary biliary cirrhosis arise from chronic biliary obstruction. Cardiac cirrhosis results from heart failure or constrictive pericarditis.

Let's shift gears to treatment. The most crucial step is abstinence from alcohol. Nutrition should include adequate calories and protein, with sodium restriction for fluid retention. Patients with hepatic encephalopathy should maintain at least 60–80 grams of protein daily. Vitamin supplementation is necessary, and muscle cramps may improve with L-carnitine, calcium, quinidine, baclofen, pickle juice, or IV albumin.

Vaccination is crucial, including HAV, HBV, pneumococcal, COVID-19, and annual influenza vaccines. Portal hypertension is managed with carvedilol, a nonselective beta-blocker. Liver transplantation remains the definitive treatment for end-stage disease.

Now, let's cover complications and their management.

Let's start with Ascites & Edema

Yes! A Diagnostic paracentesis differentiates portal hypertension-related ascites from other causes with SAAG greater than or equal to 1.1 . NSAIDs, aminoglycosides, ACE inhibitors, and ARBs should be avoided. Diuretics like spironolactone with furosemide are first-line treatment. Large-volume paracentesis which is greater than 5 Liters is an option for refractory cases. TIPS is considered in severe cases but increases the risk of encephalopathy.

How about Spontaneous Bacterial Peritonitis 

Okay, It is diagnosed with paracentesis showing Polymorphonuclear cells greater than 250 per mcL. First-line therapy is IV cefotaxime for more than 5 days, with alternatives like amoxicillin-clavulanate, levofloxacin, or piperacillin-tazobactam. Long-term prophylaxis includes ciprofloxacin or Trimethoprim- Sulfamethoxazole.

Okay, what about Hepatorenal Syndrome.

Yes! Hepatorenal syndrome is diagnosed when azotemia occurs within 48 hours or there is a 50% increase in serum creatinine within the past 7 days, along with oliguria, and the exclusion of nephrotoxic drug use, structural kidney injury, and shock, with failure to improve after 2 days of diuretic withdrawal and volume expansion using albumin. You see Oliguria, hyponatremia, and low urinary sodium concentration in such patients. Treatment includes Discontinuation of diuretics, and administering terlipressin or norepinephrine plus IV albumin. TIPS and liver transplantation are definitive solutions.

Okay, what about Hepatic Encephalopathy. 

The clinical spectrum of hepatic encephalopathy ranges from day-night reversal and mild intellectual impairment to coma, with stages including mild confusion, drowsiness, stupor, and coma. Management includes lactulose, rifaximin, and metronidazole. GI bleeding, infections, and metabolic disturbances should also be addressed.

And For Coagulopathy: Vitamin K, fresh frozen plasma, and thrombopoietin analogs like avatrombopag help correct deficits.

Now let's talk about Variceal Hemorrhage: Initial stabilization with IV fluids, octreotide, and urgent endoscopy for band ligation. Balloon tamponade and TIPS are reserved for severe cases. Nonselective beta-blockers and ligation prevent rebleeding. Liver transplantation remains the ultimate cure.

What do you do when you notice a cirrhotic patients with low pulse oximetry. 

Good question! We can suspect Hepatopulmonary Syndrome. It is characterized by a triad of chronic liver disease, an increased alveolar-arterial gradient on room air, and intrapulmonary vascular dilatations or arteriovenous communications, leading to a right-to-left intrapulmonary shunt. Symptoms include platypnea and orthodeoxia, with arterial deoxygenation worsening when upright. Diagnosis is suspected in cirrhotic patients with pulse oximetry is less than 96% and confirmed through contrast-enhanced echocardiography, macroaggregated albumin lung perfusion scanning, and high-resolution CT if necessary. Severe hypoxemia can be managed with long-term oxygen therapy, and liver transplantation may reverse HPS but carries increased postoperative risks.

And if patient develops Portopulmonary Hypertension?

Firstly, that is diagnosed via right heart catheterization and treated with prostacyclins, endothelin-receptor antagonists, and Phospho-di-esterase-5 inhibitors.

Finally, liver transplantation is indicated for progressive liver failure, acute-on-chronic failure, and select metabolic diseases. Absolute contraindications include malignancy (except small Hepatocellular Carcinoma), advanced cardiopulmonary disease, and sepsis. Relative contraindications are age greater than 70 years, obesity, and active alcohol use. MELD score prioritizes recipients.

Post-transplant care involves immunosuppressants like tacrolimus, cyclosporine, sirolimus, corticosteroids, and mycophenolate mofetil. Risks include infection, Chronic Kidney Disease, and metabolic complications like diabetes and obesity.

Thanks for joining us today!

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