Joseph Alcorn

Variants of Varices: Is It All “Downhill” from Here?

A 39-year-old male inpatient, with cerebral palsy, endstage renal disease, and previously diagnosed idiopathic non-cirrhotic portal hypertension, was seen in consultation because of an episode of melena. Ten days prior to our consultation, he was admitted for erythema overlying an arteriovenous fistula on his left forearm. Blood cultures had grown methicillin-susceptible Staphylococcus aureus that was treated with intravenous cefazolin. On the night prior to his anticipated discharge, he was noted to have black stools, prompting an evaluation of potential upper gastrointestinal bleeding. His medical record revealed repeated upper gastrointestinal endoscopic investigations of hematemesis, dating back 19 years. Until 8 years ago, only esophagitis had been noted at endoscopy, but more recently, in addition to esophagitis, he was noted to have esophageal varices and portal hypertensive gastropathy. Subsequent endoscopies had also noted that the varices extended proximally to the midand upper esophagus. He had never undergone variceal band ligation. Following his initial endoscopy, he was evaluated for the etiology of portal hypertension. Serologic data were unrevealing of the etiology of cirrhosis. The first of three liver biopsies, performed via a transjugular approach 8 years prior to admission, was notable for a sharp angulation at the superior vena cava. Although the guide wire was passed without difficulty, enabling passage of the catheter into the inferior vena cava (IVC), injection of contrast demonstrated stenosis of the superior vena cava (SVC), just below the entry of the azygos vein, with anatomical distortion due attributed to marked scoliosis. Hepatic vein pressure measurements revealed a wedge pressure of 25 mmHg and a portal-to-hepatic venous pressure gradient of 19 mmHg. Liver biopsy at this time was reported as showing increased iron deposition in Kupffer cells, but no abnormalities specific to any form of liver disease and no cirrhosis. Two years prior to the current admission, two additional percutaneous, ultrasoundguided liver biopsies again revealed Kupffer cell siderosis, but again with no increased hepatic fibrosis, sinusoidal dilation, or cirrhosis. The patient was diagnosed with noncirrhotic portal hypertension for which no risk factors were identified. Because of recurrent hematemesis, 5 years prior to the current hospitalization, a transjugular intrahepatic portosystemic shunt (TIPS) was placed. During this procedure, severe stenosis of the right innominate vein was noted, connecting with a patent but tortuous IVC whose course followed his scoliotic curvature. Following TIPS placement, the portal-to-hepatic venous gradient was decreased to 7 mmHg with cessation of hematemesis for several years. Nonetheless, 2 years prior to this hospitalization, during evaluation for the cause of melena, portal pressures became elevated. A successful revision of the TIPS was performed via the right common femoral vein (due to difficulty cannulating the SVC), with venous drainage through enlarged hemiazygos, chest, and abdominal wall collateral vessels noted. He did not experience any further gastrointestinal bleeding until the current hospitalization. L. Gessel J. Alcorn Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

Portal Hypertensive Bleeding: A Navel Approach

A 58-year old man was referred to the liver clinic with intermittent bleeding from his umbilicus. The bleeding was bright red, occurring 3 times per week for several months. During most of these episodes, he felt a sudden, warm, wet feeling in his shirt. Occasionally, the bleeding was more profuse, and on one occasion it attenuated a dinner date when, as he raised his shirt surreptitiously for inspection, a jet of blood splattered on his companion. On physical examination, he was obese, and his vital signs were within normal limits. His abdominal examination revealed mild epigastric tenderness, normal bowel sounds, and no ascites or vascular sounds. The umbilicus was prominent but there was no discharge or caput medusa. His medical history included cirrhosis of the liver ascribed to previously treated hepatitis C virus infection, heavy remote alcohol use, and nonalcoholic fatty liver disease (NAFLD) in the setting of obesity and diabetes mellitus type II. His surgical history included cholecystectomy. He complained of chronic, vague, intermittent abdominal pain. His medications included spironolactone, propranolol, losartan, metformin, baclofen, morphine, oxycodone, vitamin D, and fish oil. Laboratory tests revealed blood hemoglobin 17.5 g/ dL (normal Range [N]: 13.5–17.7), hematocrit 52.7% (N: 42–53%), and a platelet count of 103 K/mm3 (N: 150–400 K/ mm3); serum concentrations of albumin of 3.8 g/dL (N: 3.4–4.7 g/dL), total bilirubin 1.0 mg/dL (N: 0.3–1.2 mg/dL), creatinine 0.72 mg/dL (N: 0.66–1.25), and an international normalized ratio (INR) of 1.1 (N: 0.8–1.2). His calculated model for end-stage liver disease (MELD) score was 7. An ultrasound examination of the abdomen demonstrated an enlarged liver with increased echogenicity and an enlarged spleen measuring 13.84 cm in length. Surgical consultation did not identify any readily treatable source of bleeding. Evaluation by the Hepatology service prompted performance of a three-phase CT scan whose findings supported those seen on ultrasound, but which showed in addition a portal-to-systemic vein that extended from the superior mesenteric vein to the umbilicus. No ascites was apparent on either examination. The patient was referred to the department of Interventional Radiology for further evaluation and management. A successful coil insertion and an Onyx® Liquid Embolic System (LESTM) embolization (EV3-Pharmaceuticals/ Micro Therapeutics, Inc., Irvine, CA) were performed, with occlusion of the “recanalized umbilical vein” (Fig. 1). Subsequently, the patient has done well for over a year, with no further bleeding from his umbilicus. Repeat post-procedure CT images were reported to show interval embolization of the umbilical vein, images which later puzzled emergency department physicians seeing the patient but unfamiliar with his history of umbilical vein embolization (Fig. 2a, b).

A Remembrance of Procedures Past: Late Hepatic Artery Thrombosis

A 63-year-old man was evaluated in the emergency department of an outside hospital with complaints of sharp right upper quadrant abdominal pain that radiated to his back. The pain had progressed over the previous 3 days, accompanied by nausea but without fevers or chills. His past history included cirrhosis due to a-1 antitrypsin deficiency, for which he had undergone orthotopic liver transplantation (OLT) in 1997, followed by chronic immunosuppression therapy with tacrolimus. He also had had diabetes, hypertension, and papillary thyroid carcinoma treated with thyroidectomy followed by administration of I, leading to a lymphoproliferative plasmacytoma of the tongue due to radiation. His initial laboratory evaluation included a complete blood count, basic metabolic panel, and liver function tests, all of which were within normal limits. In addition, computerized tomography (CT) of his abdomen and pelvis (with contrast) demonstrated a dilated 1-cm common bile duct (CBD) unchanged from previous images (Fig. 1). The CT scan revealed diverticulosis, with possible early diverticulitis in the sigmoid and descending colon, and extensive visceral arterial atherosclerotic calcifications; the patient was discharged home on therapy with ciprofloxacin and metronidazole. Two days later he returned to the emergency department with similar complaints of progressive right upper quadrant abdominal pain. Repeat laboratory tests now demonstrated an elevated bloodWBC of 18,100/mm (normal\11,000/mm), serum concentrations of aspartate aminotransferase of 762 U/ L (normal\58 U/L), alanine aminotransferase of 571 U/L (normal\67 U/L), alkaline phosphatase of 207 U/L (normal \150 U/L), total bilirubin of 4.9 mg/dL (normal\1.2 mg/ dL), direct bilirubin of 3.1 mg/dL (normal \0.4 mg/dL), creatinine of 2.16 mg/dL (normal\1.66 mg/dL), and international normalized ratio (INR) of 1.37 (normal\1.2). Subsequently, an abdominal Doppler ultrasound showed unremarkable liver morphology but with no demonstrable flow in the hepatic artery (Fig. 2).When reread, the earlier CT images were now interpreted as revealing occlusion of the hepatic. In light of the extensive vascular calcification, without evidence of any localized collection of bile (biloma) or liver necrosis, it was felt that this occlusion could have been or uncertain duration. Nevertheless, the patient was transferred to the intensive care unit at the University of New Mexico Health Sciences Center (UNMHSC) in order to receive a higher level of care as indicated. Initial evaluation there revealed a man in mild distress due to abdominal pain: he was afebrile (37 C), had a normal heart rate (97/min), blood pressure (106/ 65 mmHg), respiratory rate (17/min), and blood oxygen saturation of 97% (on 3 L of oxygen via nasal cannula). The patient was noted to have scleral icterus and a wellhealed abdominal scar from the prior liver transplantation. He had moderate tenderness in the right upper quadrant of the abdomen without rebound tenderness or guarding. & Thomas Queen Tqueen@salud.unm.edu

Hepatic Dysfunction in Renal Cell Carcinoma: Not What You Think?

A 55-year-old Caucasian male, with history of type 2 diabetes mellitus and benign prostatic hyperplasia, was initially evaluated in emergency department with a 2-month history of worsening jaundice, pruritus, and right upper quadrant abdominal pain. His gallbladder had previously been removed. Medications included insulin and tamsulosin. He had a 20 pack-year history of smoking. He denied ever drinking alcohol to excess or using illicit drugs. On presentation, his vital signs were within normal limits. Physical examination revealed only scleral icterus, diffuse skin excoriations on the extremities and torso, and abdominal tenderness to palpation over the right upper quadrant. The liver span was normal; the spleen was not enlarged, and there was no lymphadenopathy or peripheral edema. Results of laboratory tests showed a hemoglobin (Hgb) 18 g/dl (13–17 g/dl), white blood cell (WBC) count 10 K/ mm (4–10 K/mm), platelet count 300 K/mm (150–400 K/mm), blood urea nitrogen (BUN) 20 mg/dl (8–21 mg/dl), and serum concentrations of creatinine 1.0 mg/dl (0.8–1.3 mg/dl), total bilirubin 20.9 mg/dl (0.3–1.9 mg/dl) [(conjugated bilirubin 12.5 mg/dl)], alkaline phosphatase (ALP) 327 units/l (50–100 units/l), gamma glutamyl transpeptidase (GGTP) 185 units/l (6–50 units/l), prothrombin international normalized ratio (INR) 1.6 (0.9–1.2), albumin 2.5 g/dl (3.5–5.5 g/dl), aspartate aminotransferase (AST) 29 units/l (5–30 units/l), and alanine aminotransferase (ALT) 34 units/l (5–30 units/l). Urinalysis was positive for urobilinogen and glucose, with 1 red blood cell/hpf on microscopic examination. Although an ultrasound examination of the right upper quadrant was unremarkable, abdominal computed tomography (CT) using intravenous contrast revealed an enhancing, 2.5 cm diameter, exophytic mass arising from the lower pole of the left kidney (Fig. 1). Magnetic resonance cholangiopancreatography (MRCP) was normal. The patient first underwent an ultrasound-guided liver biopsy, which revealed portal and periportal neutrophilic inflammatory infiltrates, with bile duct and ductular proliferation and centrilobular zone v3 hepato-canalicular cholestasis, findings consistent with cholestatic hepatitis. Serum concentrations of liver enzymes were unchanged during the entire hospitalization. Under the direction of the genitourinary surgical service, the patient underwent uneventful surgical resection of the renal mass. Histologic examination of the mass revealed the presence of tumor, a clear cell renal carcinoma with no vascular or capsular invasion. No obvious metastases were present, and the liver appeared grossly normal. Three months post-nephrectomy, serum concentrations of liver tests had returned to within normal limits (Fig. 2).

Dysphagia Lusoria: An Unexpected Sequelum of Cardiothoracic Surgery

An 81-year-old female inpatient was seen in consultation for dysphagia. Her past medical history included coronary artery disease complicated by atrial fibrillation and placement of a drug-eluting coronary arterial stent in 2007. Diabetes mellitus, hypertension, dyslipidemia, urinary incontinence, and a treated non-Hodgkin’s lymphoma of the right thigh were also present. About 1 month prior to our consultation, she was admitted for shortness of breath and dyspnea on exertion, symptoms that had been present for about 9 months, but had worsened for the week prior to admission. A promptly performed transthoracic echocardiogram revealed moderate-to-severe aortic stenosis. Cardiac catheterization revealed an estimated aortic valve area of 0.64 cm, non-critical two-vessel coronary artery disease with intact left ventricular function and wall motion. Two weeks prior to our consultation she underwent aortic valve replacement with a porcine valve as a consequence of these findings. Although her aortic valve leaflets, aortic annulus, and aortic root were heavily calcified, the operation was successfully completed without difficulty. Although the immediate postoperative course was uncomplicated, she reported dysphagia to solids and liquids, including saliva after oral feeding commenced. Upon further questioning, she stated that she had begun having dysphagia 5 months earlier, initially only with solid foods such as meat. After 1–2 months she also noted difficulty when swallowing soft foods as well, including mashed potatoes. She occasionally regurgitated undigested food, but denied problems with liquids. In the weeks before aortic valve replacement, she reported increased appetite but with a feeling of being unable to reach satiety. She denied weight loss, odynophagia, gastroesophageal reflux, nausea, vomiting, melena, diarrhea, constipation, fevers, or chills. Her medications included amlodipine, hydrocodone–acetaminophen, olmesartan, carvedilol, furosemide, glyburide, hydrochlorothiazide– triamterene, oxybutynin, simvastatin, and sitagliptin. She had never used tobacco, alcohol, or illicit drugs. A limited physical exam at the time of consultation revealed a wellhealing midline thoracic incision, and an expected grade II/VI systolic ejection murmur at the right upper sternal border without radiation.

When Good Medications Go Bad, Don’t DILI Dally

A 68-year-old female outpatient with a history of depression and insomnia was seen in clinic in consultation for subacute hepatitis. Approximately 1 year prior to the clinic visit, during a hospitalization at her local community hospital for hepatitis, her routine liver tests became extremely abnormal, although supplementary laboratory tests were negative (Table 1). Abdominal ultrasonography revealed an unremarkable liver appearance and the possible presence of emphysematous cholecystitis. A computed tomography (CT) scan revealed non-specific thickening of the gallbladder wall, but the liver and biliary system were unremarkable. Magnetic resonance cholangiopancreatography (MRCP) revealed a mildly elongated but otherwise normal gallbladder. A hepatobiliary iminodiacetic acid (HIDA) scan was non-diagnostic. She was discharged from the hospital due to improvement of her liver function tests. While researching her condition post discharge, she read that antidepressants could cause liver dysfunction, prompting self-discontinuation of escitalopram, a medication she had been taking for the previous 2 years and a prior period of 7 years duration. Over the next several months, her liver function continued to improve, ultimately reaching normal levels. A year later, the stress associated with the hospitalization of her husband considerably worsened her symptoms of depression. In May 2015, her psychiatrist restarted antidepressant treatment with escitalopram; pre-treatment serum aspartate transaminase (AST) = 29 U/l and serum alanine transaminase (ALT) = 40 U/l were both within normal limits. Five days after escitalopram was started, serum AST remained at 29 U/l, but serum ALT had increased to 70 U/l, prompting discontinuation of the medication. Since her liver function continued to deteriorate, she was evaluated in liver clinic almost 2 months after the initiation of escitalopram. One week prior to the visit, the serum concentrations of total bilirubin had increased to 1.8 mg/dl, alkaline phosphatase to 244 U/l, AST to 1251 U/l, and ALT to 2035 U/l (Table 2). An MRCP revealed a contracted gallbladder without obvious cholelithiasis or ductal dilation and mild hepatosplenomegaly. A thorough history revealed that her only current medications were diazepam, lorazepam, zolpidem, and fexofenadine. With the exception of the discontinued escitalopram, these medications were similar to those she had been taking a year previously. She denied any herbal supplementation, or ingestion of herbal teas or other alternative medicines. Additionally, she rarely drank alcohol and denied any kind of substance abuse. There was no family history of liver or autoimmune disease.

Trouble Spotted in the Liver

A 48-year-old man was evaluated in the gastroenterology clinic for the incidental finding of innumerable hypoattenuating liver lesions that had been visualized on a computed tomographic (CT) scan of the chest, performed during hospital admission for treatment of a community acquired pneumonia. The patient had a history of sarcoidosis stage 1, with hilar lymphadenopathy but without parenchymal lung infiltrates, diagnosed 3 years previously at an outside facility, following biopsy of enlarged mediastinal lymph nodes. The patient was on watchful waiting. He also had diabetes mellitus type II, paraplegia following a traumatic spine injury, and multiple episodes of deep vein thrombosis (DVT) for which he was taking Coumadin. He reported weight loss of 60 lb over the previous 2 years, but no night sweats or fevers during that time. He had had fever, chills, and shortness of breath immediately prior to admission, but these had improved significantly after antibiotic treatment of his pneumonia. He denied jaundice, abdominal pain, lower limb swelling, abdominal distension, nausea or vomiting, or the use of intravenous drug or of over-the-counter medications. He was unemployed, but prior to injuring his spine he had worked in an office; he had had no recent travel or contact with animals. He had no family history of liver disease, autoimmune or infectious disease, or cancer. On physical examination, his temperature was 37 C, heart rate 77/min, blood pressure 126/86 mm Hg, respiratory rate 14/min, and body mass index (BMI) 32. He was alert and oriented, without asterixis, jaundice or signs of chronic liver disease, or hepatic decompensation. The abdominal examination was normal with no distension, ascites, or organomegaly. Apart from paraplegia and loss of sensation below the umbilicus, there were no other abnormalities, except for an erythematous maculopapular rash on the right upper and left lower extremities, accompanied by palpable subcutaneous nodules surrounding these lesions. Laboratory studies revealed a white count of 4.6 K/mm (reference 4–10 K/mm), Hgb 11.7 g/dL (14.5–17.7 g/dL), Hct 38 % (42–53 %), platelets 249 K/mm (150–400 K/ mm), INR 2.6 (0.8–1.2) while on Coumadin. Serum concentrations of electrolytes were as follows: sodium 145 mmol/L (134–144 mmol/L), potassium 3.9 mmol/L (3.5–5.1 mmol/L), creatinine 0.37 mg/dL (0.8–1.3 mg/dL), calcium 13.4 mg/dL (8.4–10.4 mg/dL), phosphorus 2.3 mg/ dL (2.3–5.6 mg/dL). Results of liver tests were: serum albumin 2.8 g/dL (3.4–4.7 g/dL), total protein 7.4 g/dL (6.1–8.2 g/dL), alanine aminotransferase (ALT) 27 U/L (14–67 U/L), aspartate aminotransferase (AST) 19 U/L (6–58 U/L), alkaline phosphatase 157 unit/L (38–150 unit/ L), total bilirubin 0.5 mg/dL (0.2–1.4 mg/dL), direct bilirubin\0.1 mg/dL, erythrocyte sedimentation rate (ESR) 44 mm/h (0–21 mm/h), C-reactive protein (CR-P) 1.2 mg/ dL (\0.3 mg/dL). Serum c-glutamyl transpeptidase (GGT) concentration was not measured at this time. Further investigation of the hypercalcemia revealed serum concentrations of ionized calcium 1.9 mg/dL (1.15–1.27), 25-hydroxyvitamin D 40 mmol/L (30–100), 1,25-dihydroxyvitamin D 52 (15–75), parathyroid hormone (PTH)\3 pg/dL (11–80), and & Khaldoon Khirfan kkhirfan@salud.unm.edu

Ferritin Out a Cause of Acute Hepatitis.

A 51-year-old male was initially evaluated in the emergency department complaining of 2 days of fatigue, nausea, non-bloody emesis and small volume, bloodless, watery diarrhea occurring 6–8 times a day, not related to eating, and without sweating or flushing. He was temporarily residing at a motel where several other occupants had reported recent flu-like illnesses. His only other complaints were the perception of fever and chills 1 week prior to the onset of diarrhea, and occasional episodes of bright red blood per rectum, similar to past episodes of hemorrhoidal bleeding. He denied abdominal pain, jaundice, rashes, or joint pain. Past medical history included hemorrhoids and glucose intolerance. He did not take any medications regularly, but four or five times per week he consumed an herbal infusion provided to him by the motel owners for the treatment of his flu-like symptoms. He had a history of smoking (40 pack years), of heavy alcohol use in college, and of IV drug use 20 years prior to initial evaluation, and he still occasionally smoked marijuana. He had been imprisoned until 6 months before presentation. His family history included diabetes, alcohol abuse, and lung cancer, but no liver disease. Physical examination was unremarkable with no fever, abdominal findings, or icterus noted. Results of initial laboratory tests included hemoglobin of 18.0 g/dL, hematocrit of 54 %, international normalized ratio (INR) of 1.43, and serum concentrations of AST 1333 U/L (nl\58), ALT 1803 U/L (nl \67), direct bilirubin of 1.8 mg/dL (nl \0.4), ferritin of 26,981 ng/mL (nl \388) (subsequently reconfirmed at 32,353), and transferrin saturation of 98 % (nl \55 %). Acetaminophen was undetectable in the serum.

Portal Hypertension in Alcoholic Liver Disease: Can It Be Fixed?

A 47-year-old male with many years of heavy alcohol use was admitted for several days of worsening lower limb swelling, abdominal distension, jaundice, and watery diarrhea. He denied fever, chills, rigors, abdominal pain, or confusion. There was no history of intravenous drug use or the taking of prescription or over-the-counter medications. There was no family history of liver disease. Vital signs were unremarkable. Physical examination notable for jaundice, palmar erythema, numerous spider angiomata on the chest, abdominal distension with shifting dullness, and lower extremity edema extending to the thighs were noted. The patient was not confused and did not demonstrate asterixis. Laboratory studies were significant for WBCs 15.4/lL (4–10.6), INR 1.5 (0.8–1.2), potassium 2.9 mmol/L (3.5–5.1), creatinine 0.7 mg/dL (0.8–1.3 mg/dL), albumin 2 g/dL (3.5–4), ALT 84 U/L (12–78), AST 290 U/L (10–37), bilirubin 27.1 mg/dL (0.2–1) with direct fraction of 21.3 mg/dL (0.1–0.4). Tests for the presence of Wilson’s disease, hemochromatosis, viral hepatitis A, B, and C, autoimmune hepatitis, and hepatitis due to toxic substances were all negative. Alpha fetoprotein was 3.1 ng/mL (\15 ng/mL). Liver ultrasound was reported as showing hepatomegaly, splenomegaly, and ascites. Diagnostic paracentesis revealed findings consistent with non-infected portal hypertensive ascites. Stool tested positive for Clostridium difficile toxin by ELISA. The patient was diagnosed with Clostridium difficile colitis, alcoholic hepatitis (AH), and probable liver cirrhosis. The Model for End-Stage Disease (MELD) score was 23, and Maddrey’s Discriminant Function (DF) score was 39, indicating severe AH. Due to the elevated DF, pentoxifylline plus nutritional support was administered in preference to corticosteroid therapy due to the Clostridium difficile infection. Oral vancomycin was also initiated, together with furosemide and spironolactone for the ascites and the lower limb swelling. After several days of treatment, the diarrhea resolved, the lower limb swelling improved, and serum bilirubin concentrations improved to 24.3 mg/dL (0.2–1 mg/dL). He was discharged home with the plan to continue pentoxifylline for 28 days and to complete 14 days of oral vancomycin treatment for the severe Clostridium difficile infection. The patient continued to drink alcohol and over the following months had several admissions for ascites and worsening lower extremity swelling. Prednisone therapy was initiated due to the MELD score rising to 30 and DF score to 45. The use of diuretics was limited by serum creatinine rising to 2.2 mg/dL (0.8–1.3 mg/dL), necessitating serial therapeutic paracenteses. Given the poor prognosis with unlikely regression of his cirrhosis, palliative care evaluation was obtained without any hepatologic consultation with the patient electing hospice care with peritoneal drain placement for convenience. After enrollment in hospice, he was able to successfully discontinue alcohol and limit salt intake, and when evaluated several months later, his ascites had resolved, enabling K. Khirfan J. Alcorn Division of Gastroenterology and Hepatology, University of New Mexico School of Medicine, Albuquerque, NM, USA

An ALTernate Interpretation of Serum Transaminases

In this issue, Hee Yeon Kim et al. [1] further extend an evolving understanding of ALT reference range in ways that affirm the importance of conceiving of laboratory data as probability estimates influenced by clinical circumstances. Furthermore, their work also demonstrates latent clinical information in laboratory data that outdated methods of reporting leave untapped but which an ‘‘intelligent’’ medical laboratory could provide. While some laboratory results—have binary outcomes, others fall across a range typically distributed within a ‘‘healthy population.’’ But there are pitfalls in approaching the cutoffs as if they cleanly separate ‘‘health’’ from ‘‘disease,’’ as demonstrated by serum concentrations (levels) of alanine aminotransferase (ALT). ALT levels are not distributed normally [2], vary with race, size, and age [2, 3] and can vary widely in specificity and sensitivity for liver disease depending upon how stringently the reference range is defined [4, 5]. While the relative contributions of obesity and the commonly—but not inevitably—linked metabolic syndrome to cardiovascular disease risk are still not entirely clear [6], Kim’s article demonstrates that there may be important clinical information hiding within the normal ranges set by the laboratory. In this study, ALT levels within the established normal range but above a more stringently defined upper limit predicted the metabolic obese phenotype even in patients not themselves overtly overweight. Even for clinicians adroit at the use of standardized thresholds to interpret diagnostic testing [7], a laboratory value falling within a single reference range thus simplifies into oblivion this potentially useful information. In a paper-and-pencil era, an experienced clinician might interpret ALT in light of individual patient characteristics—ALT levels that would provoke a biopsy if