So, I want to go to a clinical case. This is a 30-year-old woman presented to the management of hypertriglycemia to an endocrine clinic, and she just had a near-death experience, hospitalization, and post-pancreatitis. So the patient and her parents are really desperate for some answers to know why she had this pancreatitis. So past medical history included history of pancreatitis in her 20s and was diagnosed at the time with hypertriglycemia over 1,000 mg per deciliter. So she already knew that she had hypertriglycemia at the time, but she didn't know why she had this disorder. And no history of gallstone problem or any abdominal procedure during or just prior to this pancreatitis episode. So no history of menstrual irregularities were noted. So her medication at the time was phenolphyllate public acid, HMG-CoA reductase inhibitor, and mPC1L1 inhibitor, which is azithromycin, and occasional omega-3 fatty acid, which is fish oil. And she also was taking over-the-counter oral contraceptive pills for birth control, not for menstrual irregularities, prescribed by OBGYN. So she implemented, or she was recommended to take low-fat diet after the first episode of pancreatitis, which she followed carefully for over 10 years until the second pancreatitis. She said she does some exercise and she's a non-smoker and rarely drinks alcohol because she knew that her triglycerides can be high with alcohol. Her family history, no reported history of hypertriglycemia, no history of cardiovascular disease or cancer. So whole family basically are healthy overall. So this incident happened prior and during hospitalization. She attended several weddings and especially receptions during the week prior to hospitalization. So she had loosened dietary regimen. She was not as regimented about strictly following the low-fat diet. She said she had pieces of cake at a couple events, but she admits only one alcohol at one event. So she didn't drink excessively during that time. Then afterwards, she started having severe and unrelenting abnormal pain. Then she came to the hospital because pain was not subsiding. Hypertriglycemia was noted over 4,000 milligrams per deciliter. So at the time, plasmapheresis was implemented to lower triglycerides and it did lower to 480 milligrams per deciliter. Because of the suspicion of pancreatitis, CT abdomen was observed and pancreatitis with extensive necrotic changes were noted. So whether or not she has a history of pancreatitis, that progress of necrotic change was so fast compared to someone who never had pancreatitis, it's unknown. But it seems like it was very severe. So she required multiple procedures, including abdominal laparotomy and bowel resection. So she had to have bowel resection, that's a big deal, requiring multiple reconstructive procedures for a prolonged ostomy use. So she went through a lot in over two months. She was discharged from the hospital after 71 days and she said she lost about 20 pounds. So this was really a life-threatening event that she just went through. So at the clinic, her features were BMI of 24.52, which is kilogram per meter square, which is within normal limits. However, she had very impressive muscularity, no apparent subcutaneous fat in arms and legs, but no acanthosis, neither can indicate insulin resistance. But interestingly, accompanying mother also was very muscular and she said she does not exercise extensively. So laboratory studies indicated glucose of 99 milligram per deciliter, that's within normal limits. Inflammation was high for that glucose level, 16.2 micro international unit per liter. And hemoglobin A1c is 5.6%, that's within the normal limits and other labs are within normal limits. She had been on nutritional supplements because of the surgery. So everything looked okay as far as laboratory studies are concerned. Tomeostatic model assessment for insulin resistance showed 4.0, so less than 2.0 is insulin sensitive. So her laboratory study for home IR indicated she's insulin resistant. So this is what she looked like. She's not a big lady, but you can see the muscular features on her arms and you can see no subcutaneous fat, so you can see the vessels from the arms and legs. So this was really the clue that gave my colleague that she has a heritable condition specifically like dystrophy. And that was a really astute observation, I believe, that we really clinched the diagnosis there. So additional evaluation was conducted. So ultrasound of abdomen showed fatty liver, which is common in lipodystrophy. DXA scan for fat quantification said total body fat of 15.6%, which is lower than normal and legs only 9%. 2D echocardiography and EKG were done because some patients with lipodystrophy develop cardiomyopathy. So these were preemptively checked and they were normal, luckily. Additional inquiry of family history revealed that maternal grandfather and two maternal uncles have similar body habits, so very muscular. So this was really a clinching information as well that this family's condition is inherited. So this is their pedigree. You can see that the patient is right here. She's the only one having the muscular features plus hypertriglyceridemia, but mother, two uncles, maternal grandfather, they all have muscular. So usually males with the muscular features may not be noticed, but then if you compare to other siblings in the family, it's clear that they know that these brothers are different from these other two brothers or sister. And she also has a brother who's not muscular like she is. So this pedigree really tells us that there is a condition inherited through the family for three generations. So summary of the notable finding, first episode of pancreatitis in early 20s. So that's really a clinching information, one of the clinching first information for heritable condition because onset is early adulthood. She might have had earlier inclination, but the first event was in her early 20s pancreatitis. And after that, low-fat diet stabilized her triglycerides. No family history of hypertriglyceridemia, but mother and several maternal family members with muscular features. So the first history part, there was a potentially familial myelomimia syndrome, maybe a diagnosis, but other features really points to lipodystrophy. So that's probably the clinical diagnosis we decided. So impressive muscularity in the arms and legs of the patient without subcutaneous fat, high HOMA-IR indicating insulin resistance without diabetes and fatty liver noted. And also the DEXA scan of the fat quantification showed low-fat percentage of total body and legs. That's all pointing to lipodystrophy. And unfortunately, she had secondary hit for hypertriglyceridemia, so dietary indiscretion and only one alcohol, but added to the combination of oral contraceptive pills. So those probably didn't really have the insult and resulted in the hypertriglyceridemia leading to pancreatitis for this episode. So this was really unfortunate. Assessment clinical diagnosis of familial partial lipodystrophy likely overlying secondary hypertriglyceride risk insult is present. And because family really wanted to know the cause, genetic testing was decided to confirm the clinical diagnosis. And the best option for this case was panel testing because at this point, we have no idea which gene is responsible for this condition for her. So we did send out for genetic testing and they had 19 genes tested in a panel. They did sequencing of the panel and they also did, they mainly did the exon and exon intron boundary. They did 10 nucleotide either way, plus the CNB analysis. So they did pretty comprehensive analysis of the genes on the panel. They said that they do not analyze the promoter area of the genes and some of the untranslated region of the nucleotide, meaning like introns, certain regions are not tested. So, but the important regions they've tested on all these genes and identified lamin A mutation, arginine changing to glutamine, and at the 482 protein, cDNA is G2A change at 1,445 nucleotide and zygosity is heterozygous. And then this is a well-known pathogenic gene mutation. There's arginine to leucine change and tryptophan change at the same location. So this is a well-known Dunnigan lipodystrophy. But very interesting that lamin A encodes for lamin A and C, which are supporting scaffolding components of nuclear envelope. That's a structure that surround the nucleus in the cell. So why does this gene mutation leads to lipodystrophy? It's still not well studied at this point. So to just summarize the case, familial partial lipodystrophy, specifically Dunnigan type was diagnosed in the patients molecularly. The patient and the parents were relieved to receive the definitive diagnosis because they were really, really distressed about not knowing the diagnosis. So this kind of gave them comfort that knowing that, you know, they have the diagnosis. They have the final diagnosis. However, you know, like the endeavor of this disorder does not end there because she has been going through a lot still. And she had gone through a lot with her second episode of pancreatitis. So recommendations were at the time discontinued OCP, lipid management with a statin HMJ-CoA inhibitor and fibric acid, nutritional concern due to complication of pancreatitis. So she had bowel resection, so that's a big deal. And this was going to continue to be a concern. Periodic monitoring of lipids, glucose, cardiac and kidneys are recommended and family screening is also recommended. So now two years later, her triglyceride is 83, but she's not really eating well, taking enough nutrients. So she's requiring supplemental total parental nutrition supplement, you know. So she overall not doing well. She has continued complication from pancreatitis episodes. She has like developed ventral hernia and fissure. I heard it's still draining and they're trying to get a surgeon to give them recommendations to what to do. And she was diagnosed with osteoporosis, probably due to a nutritional issue. But osteoporosis has been identified in patients with lipodystrophy. So there may be overlying lipodystrophy being the cause for osteoporosis and anemia due to iron deficiency. So this is a case where if we had been able to diagnose her after first episode, the second episode would not have happened. We don't know. But you know, like now finally they have the definitive diagnosis that at least they give them some comfort that they know what to do from now on, but doesn't change the fact that she had gone through the second pancreatitis, which was life-threatening and she continues to have issues afterwards. So she's only 34 years old and it's a difficult case.

clinical case

hypertriglyceridemia

pancreatitis

lipodystrophy

early diagnosis